Devices and methods for delivering opioid antagonists including formulations for naloxone

ABSTRACT

An apparatus includes a container, a needle, and an actuation assembly. The container contains a dose of a naloxone composition having a delivered volume of at least about 0.34 mL. The actuation assembly includes an energy storage member that produces a force on a movable member to move the needle and to deliver the dose of the naloxone composition. The 90% confidence interval of at least one of the relative mean maximum naloxone plasma concentration after dose delivery into the body (C max ), time to reach the maximum naloxone plasma concentration (T max ), area under the plasma concentration-time curve from pre-dose (time 0) extrapolated to infinity (AUC 0-∞ ), or area under the plasma concentration-time curve from pre-dose (time 0) to the time of the last quantifiable concentration (T last ) (AUC 0-t ) of the delivered dose to a delivered dose of a corresponding naloxone composition delivered via a manually-actuated syringe is within 80% to 125%.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of pending U.S. patent application Ser.No. 14/335,490, entitled “Devices and Methods for Delivering OpioidAntagonists Including Formulations for Naloxone,” filed Jul. 18, 2014,which is incorporated herein by reference in its entirety.

BACKGROUND

The embodiments described herein relate generally to medical devices andpharmaceutical compositions, and more particularly to a drug product forinjection of opioid antagonists, including formulations for naloxone.

Opioid antagonists are medicaments that prevent and/or reverse theeffects of opioids. Known opioid antagonists, such as naltrexone andnaloxone, can be used, for example, to treat respiratory depression andother indications that result from opioid toxicity. For example, knownformulations for naloxone can be used to reverse and/or mitigate theeffects of an overdose of a drug containing opioids, such as, forexample, heroin. In such situations, it is desirable to deliver thenaloxone formulation quickly and in a manner that will produce a rapidonset of action. Accordingly, known formulations of naloxone are oftendelivered either intranasally or via injection.

The delivery of naloxone intranasally or via injection, however, ofteninvolves completing a series of operations that, if not done properly,can limit the effectiveness of the naloxone formulation. For example,prior to delivering the naloxone, the user must first determine whetherthe patient's symptoms warrant the delivery of naloxone, and then couplea needle (or an atomizer) to a syringe containing the naloxoneformulation. After the device is prepared for delivery, the user thenselects the region of the body in which the naloxone is to be delivered,and manually produces a force to deliver the naloxone. In somesituations, such as, for example, when the patient is in an ambulance ora hospital setting, the user then inserts an intravenous catheter toadminister the naloxone. Additionally, after the delivery of thenaloxone formulation, the user must dispose of the device properly(e.g., to prevent needle sticks in instances where the naloxone isinjected) and seek further medical attention for the patient.Accordingly, known formulations of naloxone are often delivered by ahealthcare provider in a controlled environment (e.g. a hospital,physician's office, clinic or the like). Access to emergency medicalfacilities and/or trained health care providers, however, is not alwaysavailable when an individual is suffering from an overdose. Moreover,because naloxone is often administered during an emergency situation,even experienced and/or trained users may be subject to confusion and/orpanic, thereby compromising the delivery of the naloxone formulation.

The use of some known devices for delivering naloxone compositionsgenerally involves a user manually generating a force and/or pressurethat is sufficient to convey the naloxone from the device into the body.For example, to deliver naloxone using known syringes, the user manuallyinserts a needle into the body (e.g., intramuscularly) and followinginsertion, manually depresses a plunger into the syringe body. The forcegenerated by the user to insert the needle and/or manually depress theplunger, however, can vary depending on the user (e.g., based on auser's strength, comfort level, experience, etc.), thus resulting inundesirable fluctuations in the flow of the naloxone and/or incompletedelivery of the full dose. Such fluctuations and variability can beparticularly undesirable when the naloxone is being atomized forintranasal delivery. For example, in some instances, the user may beunable to generate sufficient force to provide the desired flow rateand/or flow characteristics (e.g., for an atomizer) of the naloxone.Moreover, in certain situations, a user could inadvertently insert aneedle of a syringe containing a dose of a naloxone composition at anangle relative to a target injection site, which can result in failureto deliver the dose intramuscularly. For example, in some suchsituations, the dose may be delivered subcutaneously, which can affectthe release of the drug into the body and thus, the desiredpharmacokinetics (PK) of the naloxone composition. In addition, mostmanually actuated syringes do not include an automatic retraction of theneedle and/or otherwise include a needle covering mechanism that isautomatically deployed upon removal of the needle from the body, whichcan result in inadvertent needle sticks or the like.

To mitigate at least some of the challenges presented above, some knowndevices such as, for example, autoinjectors, can be arranged toautomatically perform some or all of the steps for delivering a dose ofan opioid antagonist. Some known autoinjectors, however, deliver a doseat a much faster rate and/or at higher pressures than a manuallyactuated syringe. The higher pressure and/or faster rate of delivery canresult in a difference in the delivery of the drug, thereby affectingthe pharmacokinetic characteristics of the drug upon delivery. Similarlystated, changing the mechanism of delivery of a known drug can influencethe drug performance. In particular, studies have demonstrateddifferences in the bioavailability of an injectable drug product betweendifferent pharmaceutical delivery technologies (Bennett, Nichols,Rosenblum, & Condry, 1998; Brearly, Priestley, Leighton-Scott, &Christen, 2007; Simons, Gu, Simons, 2001). For example, the study byBennett et al. investigated midazolam administered by a conventionalsyringe and needle compared to administration via a jet injectionsystem, and found that the delivery via the jet injector produced peakmidazolam plasma concentrations over 30% faster with a significantlygreater overall peak level than delivery via the conventional syringe(Bennett, et al., 1998). Similar studies with insulin have demonstratedsubstantial pharmacokinetic differences between different deliverysystems (Kerum, Profozic, Granic, & Skrabalo, 1987; Halle, Lambert,Lindmayer, Menassa, Coutu, Moghrabi, Legendre, Legault, & Lalumiere,1986; Taylor, Home, & Alberti, 1981). More importantly, there have beenreports of undesirable outcomes as a result of choosing the wrongdelivery system for the desired clinical response. As one example, thedrug peramivir, which was being developed for seasonal flu, failed tomeet the primary endpoint in the mid-stage trial “because too-shortneedles failed to deliver the drug to the muscle in all of the patients”(Biocryst, 2007).

In the “Development of a Novel Approach to Assess Qualitative andQuantitative Dynamics Associated with the Subcutaneous or IntramuscularAdministration of Pharmaceuticals and Associated Parenteral DeliverySystems,” the kinematics of an injection by standard manual syringe iscompared with an injection by auto-injector. The dispersion of acontrast agent (iohexol) into the body after injection was observed inreal-time by the use of computed tomography (CT) scanning. It was foundthat iohexol delivered subcutaneously by an auto-injector resulted innotable qualitative and quantitative dispersion differences, including ahigher rate of iohexol loss from the extravascular tissue, as well asdifferences in early plasma exposure as compared to a pre-filled syringedelivery system.

Therefore, the effectiveness of a dose of a naloxone compositionformulated to be delivered via a manually actuated syringe can bedependent on the pharmacokinetic characteristics associated with thedelivery modality.

Thus, a need exists for improved methods and devices for deliveringopioid antagonists, such as, for example, devices that provide for atleast a partially automatic delivery of naloxone compositions whilemaintaining, for example, pharmacokinetic characteristics of deliveryvia a manually actuated syringe.

SUMMARY

In some embodiments, an apparatus includes a housing, a medicamentcontainer, a needle, and an actuation assembly. The medicament containeris disposed within the housing and contains a dose of a naloxonecomposition having a delivered volume of at least about 0.34 ml. Theactuation assembly includes an energy storage member and a movablemember. The energy storage member is configured to produce a force onthe movable member to move the needle from a first needle position, inwhich the needle is disposed within the housing, and a second needleposition, in which the needle is placed in fluid communication with themedicament container and a portion of the needle extends from thehousing. The actuation assembly is configured to deliver the dose of thenaloxone composition from the medicament container via the needle suchthat the 90% confidence interval of at least one of the relative meanmaximum naloxone plasma concentration after the dose is delivered intothe body (C_(max)), the time to reach the maximum naloxone plasmaconcentration (T_(max)), area under the concentration-time curve frompre-dose (time 0) extrapolated to infinity (AUC_(0-∞)), or area underthe concentration-time curve from pre-dose (time 0) to the time of thelast quantifiable concentration (T_(last)) (AUC_(0-t)) of the delivereddose to a delivered dose of a corresponding naloxone compositiondelivered via a manually-actuated syringe is within 80% to 125%.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-3 are schematic illustrations of a medicament delivery deviceaccording to an embodiment, in a first, a second and a thirdconfiguration, respectively.

FIGS. 4 and 5 are perspective views of a medicament delivery deviceaccording to an embodiment, in a first configuration.

FIGS. 6 and 7 are a front view and a rear view, respectively, of themedicament delivery device illustrated in FIG. 4 with a cover removed.

FIG. 8 is a front view of a portion of the medicament delivery deviceillustrated in FIG. 4.

FIG. 9 is a perspective view of a portion of the medicament deliverydevice illustrated in FIG. 4.

FIG. 10 is a perspective view of a proximal cap of the medicamentdelivery device illustrated in FIG. 4.

FIG. 11 is a top perspective view of a housing of the medicamentdelivery device illustrated in FIG. 4.

FIG. 12 is a bottom perspective view of a housing of the medicamentdelivery device illustrated in FIG. 4.

FIGS. 13 and 14 illustrate a medicament container, a medicament deliverymechanism, and a system actuator included in the medicament deliverydevice of FIG. 4.

FIGS. 15 and 16 are a top perspective view and a front view,respectively, of a base included in the system actuation assemblyillustrated in FIG. 13.

FIG. 17 is a front view of a portion of the medicament delivery deviceof FIG. 4.

FIG. 18 is an enlarged cross-sectional view of a portion of themedicament delivery device illustrated in FIG. 4, taken along the lineX₂-X₂ in FIG. 9.

FIG. 19 is a front view of the medicament container illustrated in FIG.13.

FIG. 20 is a cross-sectional view of the medicament container of FIG.19, taken along the line X₃-X₃.

FIG. 21 is a front view of the medicament container and the medicamentdelivery mechanism of FIG. 13.

FIGS. 22 and 23 are perspective views of a carrier included in themedicament delivery mechanism illustrated in FIG. 13.

FIG. 24 is a cross-sectional view of the carrier of FIG. 22, taken alongthe line X₄-X₄ in FIG. 21.

FIG. 25 is a cross-sectional view of the medicament container and themedicament delivery mechanism of FIG. 21, taken along the line X₅-X₅ inFIG. 22.

FIG. 26 is an enlarged side cross-sectional view of a portion of themedicament delivery device illustrated in FIG. 4, taken along the lineX₁-X₁ in FIG. 7.

FIGS. 27 and 28 are a front view and a side view, respectively, of aportion of an electronic circuit system of the medicament deliverydevice illustrated in FIG. 4.

FIG. 29 is a rear perspective view of an electronic circuit systemhousing of the electronic circuit system illustrated in FIG. 27.

FIG. 30 is a rear view of the electronic circuit system illustrated inFIG. 27.

FIG. 31 is a front view of a portion of the electronic circuit systemillustrated in FIG. 27.

FIG. 32 is a perspective view of a portion of the electronic circuitsystem of FIG. 27 and a portion of the medicament delivery mechanism ofFIG. 12, in a first configuration.

FIG. 33 is a front view of the medicament delivery device illustrated inFIG. 4 in a first configuration showing the electronic circuit system.

FIGS. 34-36 are front views of a portion of the electronic circuitsystem labeled as Region Z in FIG. 33 in a first, a second, and a thirdconfiguration, respectively.

FIGS. 37 and 38 are perspective views of a cover of the medicamentdelivery device illustrated in FIG. 4.

FIGS. 39-41 are a perspective view, a front view, and a bottom view,respectively, of a safety lock included the medicament delivery deviceillustrated in FIG. 4.

FIG. 42 is a cross-sectional view of the safety lock illustrated in FIG.39, taken along the line X₆-X₆ in FIG. 41.

FIG. 43 is a rear view of the medicament delivery device illustrated inFIG. 4 in a second configuration.

FIG. 44 is a rear view of the medicament delivery device illustrated inFIG. 4 in a third configuration.

FIG. 45 is a rear view of the medicament delivery device illustrated inFIG. 4 in a fourth configuration (i.e., the needle insertionconfiguration).

FIG. 46 is a top view of the medicament delivery device illustrated inFIG. 4.

FIG. 47 is a front view of a portion of the medicament delivery deviceillustrated in FIG. 4 in the fourth configuration (i.e., the needleinsertion configuration).

FIG. 48 is a cross-sectional view of the medicament delivery deviceillustrated in FIG. 4 in the fourth configuration (i.e., the needleinsertion configuration), taken along the line X₇-X₇ in FIG. 46.

FIG. 49 is a graph illustrating a relationship between pressure and atime of an injection event of the delivery device illustrated in FIG. 4.

FIG. 50 is a graph illustrating a relationship between a force and atime of an injection event of the delivery device illustrated in FIG. 4.

FIG. 51 is a cross-sectional view of the medicament delivery deviceillustrated in FIG. 4 in a fifth configuration (i.e., the fluidcommunication configuration), taken along the line X₇-X₇ in FIG. 46.

FIG. 52 is a cross-sectional view of the medicament delivery deviceillustrated in FIG. 4 in a sixth configuration (i.e., the injectionconfiguration), taken along the line X₇-X₇ in FIG. 46.

FIG. 53 is a front view of a portion of the medicament delivery deviceillustrated in FIG. 4 in the sixth configuration (i.e., the injectionconfiguration).

FIG. 54 is a front view of the medicament delivery device illustrated inFIG. 4 in a seventh configuration (i.e., the retraction configuration).

FIG. 55 is a flowchart illustrating a method of delivering an opioidantagonist to a body according to an embodiment.

FIGS. 56 and 57 are schematic illustrations of a medicament deliverydevice according to an embodiment, in a first and a secondconfiguration, respectively.

FIG. 58 is a flowchart illustrating a method of delivering an opioidantagonist to a body according to an embodiment.

FIG. 59 is a graph illustrating the mean plasma-time concentrationprofile for naloxone plasma concentration data on a linear scale.

FIG. 60 is a graph illustrating the mean plasma-time concentrationprofile for naloxone plasma concentration data on a semi-logarithmicscale.

FIG. 61 is a graph illustrating the mean plasma-time concentrationprofile for total naloxone plasma concentration data on a linear scale.

FIG. 62 is a graph illustrating the mean plasma-time concentrationprofile for total naloxone plasma concentration data on asemi-logarithmic scale.

DETAILED DESCRIPTION

Medicament delivery devices for administration of opioid antagonists andchemical compositions used within such devices are described herein. Insome embodiments, a naloxone composition can be formulated for use in adelivery device of the types shown and described herein. The naloxonecomposition includes an effective amount of naloxone (i.e.,4,5-epoxy-3,14-dihydroxy-17-(2-propenyl) morphinan-6-one), or apharmaceutically acceptable salt and/or ester thereof. As used herein,an “effective amount” Is an amount sufficient to provide a desiredtherapeutic effect. In some embodiments, the naloxone composition caninclude a pH-adjusting agent, such as, for example, at least one ofhydrochloric acid, citric acid, acetic acid, phosphoric acid, orcombinations thereof. In some embodiments, the naloxone composition caninclude one or more tonicity-adjusting agents, such as, for example, atleast one of dextrose, glycerin, mannitol, potassium chloride, sodiumchloride, or combinations thereof. In some embodiments, a medicamentcontainer can be filled with a naloxone composition that includesnaloxone or salts thereof, a tonicity-adjusting agent, and apH-adjusting agent, whereby the osmolality of the naloxone compositionranges from about 250 to about 350 mOsm and the pH ranges from about 3to about 5. Because the naloxone composition may be stored in themedicament container of a delivery device for extended periods of timeunder varying storage conditions, in some embodiments, the naloxonecomposition can include stabilizers to prevent or inhibit decompositionof the naloxone during storage. Moreover, in some embodiments, anelastomeric member disposed within a medicament container containing analoxone composition is configured to be compatible with the naloxonecomposition and can, for example, can be formulated to prevent undesiredleaching and/or reaction with the naloxone composition. In someembodiments, the elastomeric member is formulated to include a polymerand a curing agent. The polymer includes at least one of bromobutyl orchlorobutyl, and the curing agent includes at least one of sulfur ormetal compounds, e.g., metal oxides such as zinc oxide or magnesiumoxide, etc.

In some embodiments, an apparatus includes a housing, a medicamentcontainer, a needle, and an actuation assembly. The medicament containeris disposed within the housing and contains a dose of a naloxonecomposition (such as those described above) having a delivered volume ofat least about 0.34 ml. The actuation assembly includes an energystorage member and a movable member. The energy storage member isconfigured to produce a force on the movable member to move the needlefrom a first needle position, in which the needle is disposed within thehousing, and a second needle position, in which the needle is placed influid communication with the medicament container and a portion of theneedle extends from the housing. The actuation assembly is configured todeliver the dose of the naloxone composition from the medicamentcontainer via the needle such that the 90% confidence interval of atleast one of the relative mean maximum naloxone plasma concentrationafter the dose is delivered into the body (C_(max)), time to reach themaximum naloxone plasma concentration (T_(max)), area under theconcentration-time curve from pre-dose (time 0) extrapolated to infinity(AUC_(0-∞)), or area under the concentration-time curve from pre-dose(time 0) to the time of the last quantifiable concentration (T_(last))(AUC_(0-t)) of the delivered dose to a delivered dose of a correspondingnaloxone composition delivered via a manually-actuated syringe is within80% to 125%.

In some embodiments, an apparatus includes a housing, a medicamentcontainer, a needle, and an actuation assembly. The medicament containeris disposed within the housing and contains a dose of a naloxonecomposition. The dose of the naloxone composition has a delivered volumeof at least about 0.34 ml. The needle is configured to be placed influid communication with the medicament container when an end portion ofthe needle is extended outside of the housing. The actuation assemblyincludes an energy storage member and a movable member. The energystorage member is configured to produce a force on the movable member todeliver the dose of the naloxone composition from the medicamentcontainer via the needle. The actuation assembly delivers the dose ofthe naloxone composition into a body such that at least onepharmacokinetic parameter of the naloxone composition is bioequivalentto the corresponding pharmacokinetic parameter resulting from thedelivery of a corresponding dose of a corresponding naloxone compositionvia a manually actuated syringe. An amount of the corresponding dose issubstantially the same as the amount of the naloxone composition.

In some embodiments, a method for delivering a naloxone composition to abody includes placing a medicament injector against a body. Themedicament injector includes a housing, a medicament container, aneedle, and an actuation assembly. The medicament container is disposedwithin the housing and contains a dose of a naloxone composition thathas a delivered volume of at least about 0.34 ml. The needle is movablebetween a first needle position and a second needle position. A portionof the needle extends from the housing and the needle is in fluidcommunication with the medicament container when the needle is in thesecond needle position. The actuation assembly includes an energystorage member and a movable member. The method includes actuating themedicament injector such that the energy storage member produces a forceon the movable member to move the needle from the first needle positionto the second needle position and to deliver the dose of the naloxonecomposition from the medicament container via the needle into the body.The dose of the naloxone composition is delivered in a manner such thatthe 90% confidence interval of at least one of the relative mean maximumnaloxone plasma concentration after the dose is delivered into the body(C_(max)), time to reach the maximum naloxone plasma concentration(T_(max)), area under the concentration-time curve from pre-dose (time0) extrapolated to infinity (AUC_(0-∞)), or area under theconcentration-time curve from pre-dose (time 0) to the time of the lastquantifiable concentration (T_(last)) (AUC_(0-t)) of the delivered doseto a delivered dose of a corresponding naloxone composition deliveredvia a manually-actuated syringe is within 80% to 125%.

In some embodiments, an apparatus includes a housing, a medicamentcontainer, a delivery member and a medicament delivery assembly. Themedicament container is disposed at least partially within the housing,and includes an elastomeric member disposed therein. The medicamentcontainer contains a dose of a naloxone composition having a deliveredvolume of at least about 0.34 ml. The delivery member, which can be, forexample, a needle, a nozzle or the like, has a distal end portiondisposed outside of the housing. The delivery member us configured to beplaced in fluid communication with the medicament container. Themedicament delivery assembly includes a movable member and a deformableportion. The movable member is configured to receive an actuation force,and the deformable portion is configured to deform in response to theforce. The movable member is configured to move the elastomeric memberwithin the medicament container to deliver the naloxone composition intoa body via the delivery member after deformation of the deformableportion. The medicament delivery assembly is configured to deliver thedose of the naloxone composition into a body such that a confidenceinterval of at least one of a maximum naloxone plasma concentrationafter the dose is delivered into the body (Cmax), a time to reach themaximum naloxone plasma concentration (Tmax), or an area under a curveof the naloxone plasma concentration as a function of time from a firsttime after the dose is delivered into the body to a second time afteradministration (AUC) is between about 80 percent and about 125 percentof a corresponding confidence interval resulting from the delivery of acorresponding dose of a corresponding naloxone composition via amanually-actuated syringe, an amount of the corresponding dose beingsubstantially the same as an amount of the dose.

In some embodiments, a method includes placing a medicament deliverydevice against a body. The medicament delivery device includes ahousing, a medicament container, a delivery member and a medicamentdelivery assembly. The medicament container is disposed within thehousing, and includes an elastomeric member disposed therein. Themedicament container contains a dose of a naloxone composition having adelivered volume of at least about 0.34 ml. The delivery member has adistal end portion disposed outside of the housing, and is configured tobe placed in fluid communication with the medicament container. Themedicament delivery assembly includes a movable member and a deformableportion. A force is applied to the movable member of the medicamentdelivery assembly to deform the deformable portion of the medicamentdelivery assembly and move the elastomeric member within the medicamentcontainer. This causes delivery of the naloxone composition via thedelivery member into the body in a manner such that a confidenceinterval of at least one of a maximum naloxone plasma concentrationafter the dose is delivered into the body (Cmax), a time to reach themaximum naloxone plasma concentration (Tmax) or an area under a curve ofthe naloxone plasma concentration as a function of time after the doseis delivered into the body (AUC) is between about 80 percent and about125 percent of a corresponding confidence interval resulting from thedelivery of a corresponding dose of a corresponding naloxone compositionvia a manually-actuated syringe, an amount of the corresponding dosebeing substantially the same as an amount of the naloxone composition.

In some embodiments, the medicament delivery device can include anelectronic circuit system coupled to the housing. The electronic circuitsystem is configured to produce an output when the electronic circuitsystem is actuated. The output can be, for example, an audible or visualoutput related to the naloxone composition (e.g., an indication of theexpiration date, the symptoms requiring treatment with naloxone, or thelike), the use of the medicament delivery device, and/orpost-administration procedures (e.g., a prompt to call 911, instructionsfor the disposal of the device, or the like).

As used in this specification and the appended claims, the singularforms “a,” “an” and “the” include plural referents unless the contextclearly dictates otherwise. Thus, for example, the term “a member” isintended to mean a single member or a combination of members, “amaterial” is intended to mean one or more materials, or a combinationthereof. Furthermore, the words “a” or “an” and the phrase “one or more”may be used interchangeably.

As used herein, the words “proximal” and “distal” refer to directioncloser to and away from, respectively, an operator of the medicaldevice. Thus, for example, the end of the medicament delivery devicecontacting the patient's body would be the distal end of the medicamentdelivery device, while the end opposite the distal end would be theproximal end of the medicament delivery device.

As used herein, the terms “about” and/or “approximately” when used inconjunction with numerical values and/or ranges generally refer to thosenumerical values and/or ranges near to a recited numerical value and/orrange. For example, in some instances, “about 40 [units]” can meanwithin ±25% of 40 (e.g., from 30 to 50). In some instances, the terms“about” and “approximately” can mean within ±10% of the recited value.In other instances, the terms “about” and “approximately” can meanwithin ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1%, less than ±1%, orany other value or range of values therein or therebelow. The terms“about” and “approximately” may be used interchangeably.

In a similar manner, term “substantially” when used in connection with,for example, a geometric relationship, a numerical value, and/or a rangeis intended to convey that the geometric relationship (or the structuresdescribed thereby), the number, and/or the range so defined is nominallythe recited geometric relationship, number, and/or range. For example,two structures described herein as being “substantially parallel” isintended to convey that, although a parallel geometric relationship isdesirable, some non-parallelism can occur in a “substantially parallel”arrangement. By way of another example, a structure defining a volumethat is “substantially 0.50 milliliters (mL)” is intended to conveythat, while the recited volume is desirable, some tolerances can occurwhen the volume is “substantially” the recited volume (e.g., 0.50 mL).Such tolerances can result from manufacturing tolerances, measurementtolerances, and/or other practical considerations (such as, for example,minute imperfections, age of a structure so defined, a pressure or aforce exerted within a system, and/or the like). As described above, asuitable tolerance can be, for example, of ±1%, ±2%, ±3%, ±4%, ±5%, ±6%,±7%, ±8%, ±9%, ±10%, or more of the stated geometric construction,numerical value, and/or range. Furthermore, although a numerical valuemodified by the term “substantially” can allow for and/or otherwiseencompass a tolerance of the stated numerical value, it is not intendedto exclude the exact numerical value stated.

While numerical ranges are provided for certain quantities, it is to beunderstood that these ranges can include all subranges therein. Thus,the range “from 50 to 80” includes all possible ranges therein (e.g.,51-79, 52-78, 53-77, 54-76, 55-75, 70-70, etc.). Furthermore, all valueswithin a given range may be an endpoint for the range encompassedthereby (e.g., the range 50-80 includes the ranges with endpoints suchas 55-80, 50-75, etc.).

The embodiments described herein define volumes that contain a gas(e.g., air or the like). The gas contained within the volumes can havecharacteristics (e.g., pressure, temperature, etc.) that are dependenton, for example, a point in time during an injection event and/or thelike. Similarly, the volumes so defined can also be dependent on time(e.g., the volumes can increase or decrease over time). In general,fluid dynamic principles can be used to determine and/or define suchcharacteristics and/or relationships therebetween. For example, thedevices described herein define volumes that contain and/or receive air,nitrogen, argon, or other gases, which, in fluid dynamics, are generallyconsidered to be an “ideal gas.” As such, characteristics of the subjectgas can be determined and/or approximated using the ideal gas lawmathematically expressed below:

PV=nRT

where P is pressure, V is volume, n is the number of moles of the gas, Ris the gas constant (8.3145 Joules per moles-Kelvin (J/mol·K)), and T istemperature.

As used herein, the ideal gas law can be applied to determine arelationship between two volumes of the same gas (e.g., air).Specifically, when assuming a substantially constant temperature andconsidering that the volumes contain the same gas, the terms “nRT” (fromthe ideal gas law) are substantially equal and thus, a relationshipsbetween the two volumes can be defined as P₁V₁=P₂V₂. In this manner,when portions of the devices described herein have a predeterminedpressure and volume at a time prior to an injection event (e.g., P₁V₁),a pressure and a volume (e.g., P₂V₂) of the portions at a given timeduring an injection event can be determined and/or approximated.

The embodiments described herein can be formed or constructed of one ormore biocompatible materials. Examples of suitable biocompatiblematerials include metals, glasses, ceramics, or polymers. Examples ofsuitable metals include pharmaceutical grade stainless steel, gold,titanium, nickel, iron, platinum, tin, chromium, copper, and/or alloysthereof. A polymer material may be biodegradable or non-biodegradable.Examples of suitable biodegradable polymers include polylactides,polyglycolides, polylactide-co-glycolides (PLGA), polyanhydrides,polyorthoesters, polyetheresters, polycaprolactones, polyesteramides,poly(butyric acid), poly(valeric acid), polyurethanes, and/or blends andcopolymers thereof. Examples of non-biodegradable polymers includenylons, polyesters, polycarbonates, polyacrylates, polymers ofethylene-vinyl acetates and other acyl substituted cellulose acetates,non-degradable polyurethanes, polystyrenes, polyvinyl chloride,polyvinyl fluoride, poly(vinyl imidazole), chlorosulphonate polyolefins,polyethylene oxide, and/or blends and copolymers thereof.

As used herein, the terms “bioequivalent,” “bioequivalence,”“bioequivalency,” when used to describe to compositions generally meansthe compositions and the PK characteristics of the compositions aresubstantially the same. More specifically, the term “bioequivalence” isdefined by the Food and Drug Administration (FDA) as, “the absence of asignificant difference in the rate and extent to which the activeingredient or active moiety in pharmaceutical equivalents orpharmaceutical alternatives becomes available at the site of drug actionwhen administered at the same molar dose under similar conditions in anappropriately designed study.”

In certain embodiments, a first dosage form and a second dosage form arebioequivalent if the 90% confidence interval of the relative meanC_(max) of the second dosage form to the first dosage form is within 80%to 125%. In further embodiments, a first dosage form and a second dosageform are bioequivalent if the 90% confidence interval of the relativemean AUC_((0-t)) of the second dosage form to the first dosage form iswithin 80% to 125%. In yet further embodiments, a first dosage form anda second dosage form are bioequivalent if the 90% confidence interval ofthe relative mean AUC_((0-∞)) of the second dosage form to the firstdosage form is within 80% to 125%. In still further embodiments of theinvention, a first dosage form and a second dosage form arebioequivalent if the 90% confidence intervals of the relative meanC_(max), AUC_((0-t)), and AUC_((0-∞)) of the second dosage form to thefirst dosage form is within 80% to 125%.

As used herein, AUC_((0-∞)) is the area under the plasmaconcentration-time curve from pre-dose (time 0) extrapolated toinfinity.

As used herein, AUC_((0-t)) is the area under the plasmaconcentration-time curve from pre-dose (time 0) to the time of the lastquantifiable concentration (T_(last)).

As used herein, C_(max) is the maximum plasma naloxone concentrationdetermined directly from the plasma concentration-time profile.

As used herein, T_(max) is the time of maximum plasma naloxoneconcentration determined directly from the plasma concentration-timeprofile.

As used herein, the term “pharmacokinetic” refers generally to thecharacteristic interactions of a drug and the body in terms of theabsorption, distribution, metabolism, and excretion of the drug. By wayof example, the terms “pharmacokinetic parameter” or “pharmacokineticparameters” can include, but are not limited to parameters such asC_(max), T_(max), AUC_((0-t)), and AUC_((0-∞)).

FIGS. 1-3 are schematic illustrations of a medicament delivery device1000 according to an embodiment in a first, second, and thirdconfiguration, respectively. The medicament delivery device 1000 (alsoreferred to herein as “delivery device” or a “drug product”) includes ahousing 1100, a medicament container 1200, a needle 1360, and anactuation assembly 1300. The housing 1100 can be any suitable size,shape, or configuration and can be made of any suitable material. Forexample, in some embodiments, the housing 1100 is an assembly ofmultiple parts formed from a plastic material that are coupled togetherto form a substantially rectangular shape when assembled. In someembodiments, the parts and/or components of the housing 1100 can becoupled via, for example, ultrasonic welding, friction welding, anadhesive, an epoxy, and/or the like. In some embodiments, at least someof the parts of the housing 1100 can be coupled together to formsubstantially fluid tight seals or the like. In such embodiments, thehousing 1100 can define, for example, volumes and/or portions thatdefine a flow path through which a fluid can flow from one portion ofthe housing 1100 to a different portion of the housing 1100, asdescribed in further detail herein.

As shown in FIGS. 1-3, the medicament container 1200 is disposed withinthe housing 1100 and can be moved between a first position and a secondposition within the housing 1100 in response to an applied force (e.g.,exerted by the actuation assembly 1300). Although the medicamentcontainer 1200 is shown as moving between the first position and thesecond position to facilitate needle insertion and medicament delivery,in other embodiments, a device and/or drug product can include amedicament container that does not move relative to the housing. Themedicament container 1200 can be any container suitable for storing themedicament. In some embodiments, the medicament container 1200 can be,for example, a vial, cartridge, ampule, prefilled syringe or the likeformed from a biocompatible material such as, for example, apharmaceutical grade metal or alloy, glass, polymer, ceramic, and/or thelike. The medicament container 1200 can have, for example, a proximalend portion and a distal end portion and can define an inner volume.

The inner volume of the medicament container 1200 can include, receive,and/or otherwise contain (i.e., is filled or partially filled with) amedicament 1220 such as, for example, an opioid antagonist. Morespecifically, in some embodiments, the medicament 1220 disposed withinthe medicament container 1200 can be a naloxone composition such asthose described herein. For example, the naloxone composition caninclude an effective amount of naloxone (i.e.,4,5-epoxy-3,14-dihydroxy-17-(2-propenyl) morphinan-6-one), or apharmaceutically acceptable salt and/or ester thereof. In someembodiments, the naloxone composition can include one or morepH-adjusting agents (e.g., at least one of hydrochloric acid, citricacid, acetic acid, phosphoric acid, or combinations thereof), one ormore tonicity-adjusting agents (e.g., at least one of dextrose,glycerin, mannitol, potassium chloride, sodium chloride, or combinationsthereof), one or more stabilizing agents, and/or the like. In someembodiments, the naloxone composition can have an osmolality betweenabout 250 to about 350 mOsm and a pH between about 3 to about 5.

The medicament container 1200 can include an elastomeric member (alsoreferred to herein as a “plunger”) that can be formulated to becompatible with the medicament housed within the medicament container1200 (i.e., the naloxone composition). Similarly stated, the elastomericmember can be formulated to minimize any reduction in the efficacy ofthe medicament 1220 that may result from contact (either direct orindirect) between the elastomeric member and the medicament 1220. Forexample, in some embodiments, the elastomeric member can be formulatedto minimize any leaching or out-gassing of compositions that may have anundesired effect on the medicament 1220. The elastomeric member isdisposed within the medicament container 1200, for example, to seal theproximal end portion thereof. In some embodiments, the elastomericmember can be formulated to maintain its chemical stability,flexibility, and/or sealing properties when in contact (either direct orindirect) with a medicament 1220 over a long period of time (e.g., forup to six months, one year, two years, five years, or longer). In someembodiments, the elastomeric member can be any of the elastomericmembers shown and described in U.S. Pat. No. 8,627,816 entitled“Medicament Delivery Device for Administration of Opioid AntagonistsIncluding Formulations for Naloxone,” which is incorporated herein byreference in its entirety.

The needle 1360 of the delivery device 1000 can be any suitable shape,size, or configuration. For example, the needle 1360 can have anydiameter and/or length to facilitate the injection of the medicament1220 (i.e., the naloxone composition). In some embodiments, the needle1360 can have a length suitable to penetrate clothing and deliver themedicament via an intramuscular injection. In some embodiments, theneedle 1360 can have a length of greater than about 1 inch, greater thanabout 1.5 inches, greater than about 2 inches, greater than about 2.5inches or greater than about 3 inches. In other embodiments, the needle1360 can have a length of less than about 1 inch. Moreover, the needle1360 can have any suitable outer diameter and/or inner diameter (i.e., adiameter of a lumen defined by the needle 1360). For example, the needle1360 can have a lumen diameter of approximately between 19-gauge and31-gauge.

The needle 1360 is movable between a first needle position and a secondneedle position relative to the housing 1100. More specifically, thefirst needle position is, for example, a proximal position in which theneedle 1360 is disposed in the housing 1100 (see e.g., FIG. 1) and thesecond needle position is, for example, a distal position in which aportion of the needle 1360 is disposed substantially outside of thehousing 1100 (see e.g., FIGS. 2 and 3). In addition, the arrangement ofthe medicament container 1200 and the needle 1360 within the housing1100 can be such that the needle 1360 is fluidically isolated from themedicament 1220 contained in the medicament container 1200 when theneedle 1360 is in the first needle position and the needle 1360 isplaced in fluid communication with the medicament 1220 contained in themedicament container 1200 when the needle 1360 is in the second needposition. Thus, the medicament 1220 can be expelled through the needle1360, as described in further detail herein. In other embodiments,however, the needle 1360 can be in fluid communication with themedicament container 1200 when the needle is in both the first needleposition and the second needle position. For example, in someembodiments, the medicament container 1200 can a prefilled syringe witha staked needle that remains in fluid communication with the interiorvolume of the syringe regardless of the needle position.

Although not shown in FIGS. 1-3, in some embodiments, the needle 1360can be coupled to, for example, a carrier or the like and maintained ina substantially fixed position relative thereto. The carrier can bemovably disposed in the housing, for example, between a proximalposition and a distal position. Expanding further, with the needle 1360maintained in a substantially fixed position relative to the carrier,the proximal position of the carrier within the housing can beassociated with the first needle position and the distal position of thecarrier within the housing can be associated with the second needleposition. The carrier can also be in contact with and/or can otherwisecarry the medicament container 1200, which can be movable in an axialdirection relative to the carrier. For example, the medicament container1200 can be disposed within a portion of the carrier and movable in theaxial direction between a proximal position relative to the carrier anda distal position relative to the carrier. Therefore, the arrangement ofthe medicament container 1200, the needle 1360, and the carrier can besuch that when the medicament container 1200 is in its proximal positionrelative to the carrier and the needle 1360 is in the first needleposition, the needle 1360 is fluidically isolated from the medicament1220 contained in the medicament container 1200. Conversely, when theneedle 1360 is in the second needle position and the medicamentcontainer 1200 is placed in its distal position relative to the carrier,the needle 1360 is placed in fluid communication with the medicament1220 contained in the medicament container 1200, as described in furtherdetail herein.

The actuation assembly 1300 of the medicament delivery device 1000 canbe any suitable assembly, mechanism, and/or device that can beconfigured, for example, to move a portion of the medicament container1200 and/or the needle 1360 relative to the housing 1100. As shown inFIGS. 1-3, the actuation assembly 1300 includes a movable member 1330and an energy storage member 1410. The movable member 1330 is movablydisposed within the housing 1100 such that, a distal portion of themovable member 1330 is in contact with the medicament container 1200. Inthis manner, a force can be exerted (e.g., a force produced by theenergy storage member 1410) to move the movable member 1330substantially concurrently with medicament container 1200 (see e.g.,FIG. 2) and/or the needle 1360 or relative to the medicament container1200 and the needle 1360 (see e.g., FIG. 3).

The energy storage member 1410 of the actuation assembly 1300 can be anysuitable device or mechanism that, when actuated, produces a force tomove the needle 1360 from the first needle position (FIG. 1) to thesecond needle position (FIGS. 2 and 3) and/or to deliver the medicament1220. For example, in some embodiments, the energy storage member 1410can be a mechanical energy storage member, such as a spring; a devicecontaining compressed gas; a device containing a vapor pressure-basedpropellant; and/or the like. In some embodiments, the energy storagemember 1410 can be and/or can otherwise include an electrical energystorage member, such as a battery, a capacitor, a magnetic energystorage member, and/or the like. In other embodiments, the energystorage member 1410 can be a chemical energy storage member, such as acontainer containing two substances that, when mixed, react to produceenergy. The energy storage member 1410 can be disposed within thehousing in any position and/or orientation relative to the medicamentcontainer 1200. In some embodiments, for example, the energy storagemember 1410 can be positioned within the housing 1100 spaced apart fromthe medicament container 1200. Moreover, in some embodiments, the energystorage member 1410 can be positioned such that a longitudinal axis ofthe energy storage member 1410 is offset from a longitudinal axis of themedicament container 1200. In other embodiments, the energy storagemember 1410 can substantially surround the medicament container 1200. Inthis manner, the energy storage member 1410 can be any suitable device,mechanism, and/or member configured to exert a force on the movablemember 1330 to deliver the medicament 1220 from the medicament container1200 to the body of the patient via the needle 1360.

As shown in FIG. 1, in some instances, the delivery device 1000 can bestored in the first configuration in which the needle 1360 is in thefirst needle position. In the event of a medical emergency associatedwith, for example, a patient experiencing an opioid overdose, a user(e.g., a patient, a friend or family member, an untrained bystander, amedical professional, etc.) can manipulate the delivery device 1000 toadminister the medicament 1220 (e.g., an opioid antagonist such as anyof the naloxone formulations described herein) to the patient. As shownin FIG. 2, the user can manipulate the delivery device 1000 to actuatethe actuation assembly 1300, for example, by placing at least a portionof the delivery device 1000 in contact with a surface of the body of thepatient, and transitioning the delivery device 1000 to the secondconfiguration. The delivery device 1000 can be actuated (or transitionedto its second configuration) by any suitable mechanism, such as, forexample, by depressing the distal end surface of the delivery device1000 against the surface S, by depressing a button disposed at aproximal end of the device, or the like.

More specifically, the actuation assembly 1300 can be actuated such thatthe energy storage member 1410 exerts a force F₁ on the movable member1330 sufficient to move the needle 1360 from the first needle positionto the second needle position, as indicated by the arrow AA in FIG. 2.In some embodiments, the force F₁ exerted on the movable member 1330moves at least the movable member 1330, the medicament container 1200,and the needle 1360 substantially concurrently. With the needle 1360 inthe second needle position, a portion of the needle 1360 extends in thedistal direction from the housing 1100. Moreover, with the deliverydevice 1000 in contact with the surface of the body of the patient andwith the needle 1360 in the second needle position, a portion (i.e., adistal end portion) of the needle 1360 extends through a subcutaneousportion S of the body and into an intramuscular portion I of the body.

With the medicament container 1200 in its distal position and with theneedle 1360 in the second needle position, at least a portion of theforce exerted by the energy storage member 1410 on the movable member1330 (represented as F₂ in FIG. 3) can move the movable member 1330relative to the medicament container 1200, as shown in FIG. 3. Thus, themovement of the movable member 1330 increases a pressure within aportion of the medicament container 1200 (for example, between anelastomeric member and a surface of the medicament container 1200through which the needle 1360 extends). Thus, the portion of the forceF₂ can act to expel the medicament 1220 from the medicament container1200, as indicated by the arrow CC in FIG. 3. Although described asincluding an elastomeric member that is distinct from the movable member1330, in some embodiments, the movable member 1330 can be theelastomeric member (i.e., the plunger or “stopper” in the medicamentcontainer). In such embodiments, the energy storage member 1410 canproduce a force to act directly or indirectly on the elastomeric member(i.e., the movable member 1330) to perform the functions describedherein.

The arrangement of the energy storage member 1410, the needle 1360, andthe composition of the medicament 1220 and/or any other suitable portionof the delivery device 1000 (or drug product) can be such that themedicament 1220, when delivered, provides a desired set of deliveryand/or pharmacokinetic (PK) characteristics. In some embodiments, thespecific characteristics of the delivery device 1000 (or drug product)are such that a dose of the medicament 1220 (i.e., the naloxoneformulation) is delivered from the medicament container 1200 and intothe body of the patient (as indicated by the arrow CC in FIG. 3) suchthat at least one pharmacokinetic parameter of the naloxone compositionis bioequivalent to the corresponding pharmacokinetic parameterresulting from the delivery of a corresponding dose of a correspondingnaloxone formulation via a manually-actuated syringe. Similarly stated,the delivery device 1000 (or drug product) is configured such thatdelivery of the medicament 1220 (i.e., the naloxone formulation) fromthe medicament container 1200 to the body provides naloxonebioavailability that is bioequivalent to naloxone bioavailabilityresulting from the delivery of a corresponding naloxone formulation froma manually actuated syringe. In some embodiments, the actuation assembly1300 is configured to deliver the dose of the medicament 1220 (i.e., thenaloxone formulation) into the body such that the 90% confidenceinterval of at least one of the relative mean maximum naloxone plasmaconcentration after the dose is delivered into the body (C_(max)), timeto reach the maximum naloxone plasma concentration (T_(max)), area underthe plasma concentration-time curve from pre-dose (time 0) extrapolatedto infinity (AUC_(0-∞)), or area under the plasma concentration-timecurve from pre-dose (time 0) to the time of the last quantifiableconcentration (T_(last)) (AUC_(0-t)) of the delivered dose to adelivered dose of a corresponding naloxone composition delivered via amanually-actuated syringe is within 80% to 125%.

In yet other embodiments, the specific characteristics of the deliverydevice 1000 (or drug product) are such that a dose of the medicament1220 (i.e., the naloxone formulation) is delivered from the medicamentcontainer 1200 and into the body of the patient such that the 90%confidence interval of at least one of the relative mean maximumnaloxone plasma concentration after the dose is delivered into the body(C_(max)), time to reach the maximum naloxone plasma concentration(T_(max)), area under the plasma concentration-time curve from pre-dose(time 0) extrapolated to infinity (AUC_(0-∞)), or area under the plasmaconcentration-time curve from pre-dose (time 0) to the time of the lastquantifiable concentration (T_(last)) (AUC_(0-t)) of the delivered doseto a delivered dose of a corresponding naloxone composition deliveredvia a manually-actuated syringe is within 80% to 125%.

For example, in some embodiments, the actuation assembly 1300 isconfigured to deliver a dose of the naloxone composition (i.e., any ofthe naloxone compositions described herein) having a delivered volume ofat least about 0.34 ml at a faster delivery rate and/or at a higherdelivery pressure than would result from the delivery of a correspondingdose via a manually-actuated syringe. As described in the examplesherein, such faster delivery rate and/or higher delivery pressures canbe implemented to produce certain desired performance characteristicsassociated with the delivery device 1000 (or drug product). Suchcharacteristics can include, for example, a minimum time for insertionof the needle 1360, a repeatable needle insertion depth, repeatableplacement of the needle 1360 into fluid communication with themedicament container 1200, a consistent delivery volume, and the like.As further described herein, unexpectedly, even when delivered at afaster delivery rate and/or higher delivery pressure, the deliverydevice 1000 (or drug product) delivers the dose of the naloxonecomposition such that at least one pharmacokinetic parameter of thenaloxone composition is bioequivalent to the correspondingpharmacokinetic parameter resulting from the delivery of a correspondingdose of a corresponding naloxone formulation via a manually-actuatedsyringe.

By way of an example, in some embodiments the energy storage member 1410is and/or otherwise includes a container or a device containing acompressed gas to produce a force to move the needle 1360 and deliverthe dose of the naloxone composition 1220. In such embodiments, thearrangement of the housing 1100 can be such that portions of the housing1100 form a fluid flow path through which the compressed gas can flowafter the energy storage member 1410 has been actuated (e.g., afterpuncturing a seal and/or otherwise releasing at least a portion of thecompressed gas from the container). Moreover, a proximal end portion ofthe movable member 1330 can include a seal member or the like that canbe in contact with an inner surface of a portion of the housing 1100such that a substantially fluid-tight seal is defined therebetween.Thus, at least a portion of the housing 1100 can define an inner volumethat is substantially fluidically isolated from a remaining volumedefined by the housing 1100 and/or other structure of the deliverydevice 1000. As such, when the delivery device 1000 is actuated, thecompressed gas flows from the container having a relatively small volumeand a relatively high pressure into the inner volume of the portion ofthe housing 1100 having a relatively large volume and a relatively lowpressure (e.g., atmospheric pressure).

The expansion of the gas as it enters the substantially fluidicallysealed inner volume of the portion of the housing 1100 exerts the forceF₁ on the movable member 1330 to move the needle 1360 from the firstneedle position (FIG. 1) to the second needle position (FIGS. 2 and 3).Similarly, a portion of the force (identified as F₂) resulting from theexpansion of the gas can move the movable member 1330 relative to themedicament container 1200 to deliver the medicament 1220 (e.g., analoxone composition, such as those described herein) contained withinthe medicament container 1200 into a body of a patient via the needle1360, as described in further detail herein. A volume of thesubstantially fluidically sealed portion of the housing 1100 increasesas the movable member 1330 is moved relative to the housing 1100 inresponse to the force exerted by the expansion of the gas. Thus, apressure within the inner volume of the housing decreases as the volumeincreases in response to the movement of the movable member 1330 (e.g.,as determined by, for example, the ideal gas law expressed as P₁V₁=P₂V₂,wherein P is pressure and V is volume). Thus, the force F₂ exerted bythe energy storage member 1410 (i.e., in this embodiment, the expansionof the gas) on the movable member 1330 decreases from a first amount atthe start of an injection event to a second amount at the end of aninjection event. In some embodiments, the force exerted on the movablemember 1330 can decrease in a substantially linear manner from the firstamount at the start of the injection event to the second amount at theend of the injection event. In other embodiments, the decrease in theforce can be non-linear, exponential, and/or logarithmic over theduration of the injection event. Because of the decrease in theinjection force F₂, in some embodiments, the actuation assembly 1300 canbe configured to produce a higher initial injection force to ensure thatthe desired delivered volume is delivered having the desiredcharacteristics (e.g., that the delivered volume is repeatably deliveredwithin a desired tolerance, that the needle 1360 is repeatably placedinto fluid communication with the medicament container 1200, that thereis no “dribbling” at the end of delivery due to a drop in the injectionforce, or the like).

In contrast, a force exerted on a plunger of a manually-actuated syringeto deliver a medicament contained therein can be substantially constantthroughout the stroke of the syringe. Moreover, the force exerted on theplunger of a manually-actuated syringe to deliver the medicament isindependent from a force exerted to insert the needle into the patient.The forces exerted by the energy storage member 1410 (F₁ and F₂),however, are not independent and are not constant. Thus, in someinstances, the larger force (i.e., F₁) is exerted at the start of aninjection event to ensure proper insertion of the needle 1360 while thesmaller force (e.g., F₂) is exerted at the end of the injection event todeliver of the dose of the medicament 1220. As described herein,unexpectedly, even when delivered with a different injection and/orforce profile, the delivery device 1000 (or drug product) delivers thedose of the naloxone composition such that at least one pharmacokineticparameter of the naloxone composition is bioequivalent to thecorresponding pharmacokinetic parameter resulting from the delivery of acorresponding dose of a corresponding naloxone formulation via amanually-actuated syringe.

While the energy storage member 1410 is described above as being adevice containing a compressed gas, in other embodiments, the energystorage member 1410 can be a mechanical member such as, for example, aspring or the like. In some embodiments, the spring can be configured toexert a substantially constant force throughout an injection event. Inother embodiments, the spring can be configured to exert a varied forcedependent on a time during an injection event (e.g., which can resultfrom the changing length of the spring). Moreover, the energy storagemember 1410, so configured, can exert a force that is such that themedicament 1220 is delivered with the desired PK characteristics asdescribed herein.

Although not shown in FIG. 1, in some embodiments, the delivery device1000 can include the can include a retraction member or the like. Theretraction member can be any suitable device and/or mechanism configuredto move the needle 1360 from the second needle position toward the firstneedle position. More specifically, the retraction member can be, forexample, an energy storage member and/or a bias member that, onceactuated, exerts a force to move the needle 1360 from the second needleposition to the first needle position. In some embodiments, at least aportion of the force exerted by the energy storage member 1410 (e.g.,the force F₁) can transition the retraction member from a firstconfiguration having a first amount of potential energy to a secondconfiguration having a second, larger amount of potential energy. Thus,when the potential energy of the retraction member is greater than theforce exerted by the energy storage member 1410 (e.g., the force F₂ atthe end of an injection event), the retraction spring can exert a forcein substantially the opposite direction (i.e., opposite to the directionindicated in FIG. 3 by the arrow BB) associated with the transition ofthe potential energy to a kinetic energy, thereby moving the needle 1360towards the first needle position to be disposed within the housing1100. In this manner, the likelihood of an inadvertent needle stick orthe like can be reduced or substantially eliminated.

In some embodiments, the retraction member can be preloaded with apredetermined amount force. In such embodiments, the retraction membercan exert a force on the medicament container 1200 and/or on a carrier(as described above) supporting the medicament container 1200 that issufficient to prevent a distal movement of the medicament container 1200and/or the needle 1360 in response, for example, to gravity or the like,prior to the actuating of the actuation assembly 1300. Moreover, themedicament container 1200 and/or the carrier can include a lockingfeature of the like that can engage a portion of the housing 1100 tosubstantially limit a proximal movement of the medicament container1200, the needle 1360, the movable member 1330, and/or the retractionmember prior to actuating the actuation assembly 1300.

In some embodiments, a medicament delivery device or drug product can beconfigured to automatically deliver a medicament such as, for example,an opioid antagonist, contained within a medicament container. Forexample, FIGS. 4-52 show a medicament delivery device 2000, according toan embodiment. FIGS. 4 and 5 are perspective views of the medicamentdelivery device 2000 (also referred to herein as “delivery device” or“drug product”) in a first configuration (i.e., prior to use). Thedelivery device 2000 includes a housing 2100 (see e.g., FIGS. 6-12), asystem actuation assembly 2500 (see e.g., FIGS. 13-18), a medicamentcontainer 2200 containing a medicament 2220 (see e.g., FIGS. 19 and 20),a medicament delivery mechanism 2300 (see e.g., FIGS. 22-26), anelectronic circuit system 2900 (see e.g., FIGS. 27-36), a cover 2190(see e.g., FIGS. 37 and 38), and a safety lock 2700 (see e.g., FIGS.39-42). A discussion of the components of the delivery device 2000 willbe followed by a discussion of the operation of the delivery device2000.

As shown in FIGS. 6-12, the housing 2100 has a proximal end portion 2101and a distal end portion 2102. The proximal end portion 2101 of thehousing 2100 is fixedly coupled to a proximal cap 2103 (see e.g., FIG.10) and the distal end portion 2102 of the housing 2100 engages and/oris selectively or at least temporarily coupled to a base 2510 includedin the system actuation assembly 2500 and the safety lock 2700, asdescribed in further detail herein. The housing 2100 defines a firststatus window 2130 and a second status window 2160 (see e.g., FIGS.6-9). The first status window 2130 defined by the housing 2100 islocated on a first side of the housing 2100, and the second statuswindow 2160 of the housing 2100 is located on a second side of thehousing 2100. The status indicator windows (or apertures) 2130, 2160 canallow a patient to monitor the status and/or contents of the medicamentcontainer 2200 contained within the housing 2100. For example, byvisually inspecting the status windows 2130, 2160, a patient candetermine whether the medicament container 2200 contains a medicament2220 and/or whether the medicament 2220 has been dispensed. Morespecifically, in some instances, the status windows 2130 and 2160 canallow a patient and/or user to monitor the status and/or position of,for example, a plunger or the like disposed in the medicament container2200. Thus, based on the position of the plunger the patient and/or usercan determine the status of the delivery device 2000. In someembodiments, the delivery device 2000 (e.g., the housing 2100, themedicament container 2200, and/or any other suitable structure) caninclude a status indicator, which is viewable through the statusindicator apertures 2130 and is configured to change one or morecharacteristics thereof over time (e.g., color, image, and/or the like).

The proximal end portion 2101 of the housing 2100 includes a set ofcover retention protrusions 2104 (see e.g., FIGS. 5 and 7) and a speakerprotrusion 2138 (see e.g., FIG. 9). The cover retention protrusions 2104are configured to be received within corresponding openings 2193 definedby the cover 2190 (see e.g., FIG. 5) to at least temporarily retain thecover 2190 in a substantially fixed position about the housing 2100. Inthis manner, as described in more detail herein, the cover 2190 can beremovably coupled to and disposed about at least a portion of thehousing 2100. The speaker protrusion 2138 extends from a surface of thehousing 2100 and can maintain a position of an audio output device 2956of the electronic circuit system 2900 relative to the housing 2100 whenthe electronic circuit system 2900 is attached to the housing 2100, asdescribed herein.

The proximal end portion 2101 of the housing 2100 is fixedly coupled toa proximal cap 2103 (see e.g., FIGS. 4-10). More particularly, theproximal end portion 2101 of the housing 2100 includes a proximalsurface 2106 that includes and/or that defines a surface finishconfigured to facilitate the coupling of the proximal end portion 2101of the housing 2100 to the proximal cap 2103. For example, as shown inFIG. 11, the proximal surface 2106 can define and/or can include asurface finish or the like with a track of protrusions and/ordiscontinuities. During a manufacturing process or the like, theproximal cap 2101 can be disposed adjacent to the proximal surface 2106and coupled thereto via, for example, ultrasonic welding, frictionwelding, an adhesive, and/or the like. Thus, the track of protrusionsand/or discontinuities can be transitioned, for example, from a firstphysical state (e.g., a solid physical state) to a second physicallystate (e.g., an amorphous physical state), in which the track ofprotrusions and/or discontinuities is at least partially reconstituted,thereby fixedly coupling (i.e., welding) the proximal cap 2103 to theproximal surface 2106 of the housing 2100. Moreover, the arrangement ofthe track of protrusions and/or discontinuities of the proximal surface2106 can be such that portions of the coupling between the proximalsurface 2106 and the proximal cap 2103 form a substantially fluid tightseal while other portions of the proximal surface 2106 (e.g., portionsof the proximal surface 2106 not including the track of protrusionsand/or discontinuities) do not form a substantially fluid tight sealwith the proximal cap 2103, as described in further detail herein.

As shown in FIG. 10, the proximal cap 2103 includes a retention member2580 and defines a passageway 2156. The retention member 2580 isconfigured to receive and/or retain an energy storage member 2410 suchas, for example, a device containing a compressed and/or pressurized gas(see e.g., FIG. 13). As described in further detail herein, in thisembodiment, the energy storage member 2410 is a device containing acompressed and/or pressurized gas, when the delivery device 2000 isactuated, pressurized gas from the energy storage member 2410 (alsoreferred to herein as “gas container 2410”) is conveyed from the gascontainer 2410 and into portions of the housing 2100 via the gaspassageway 2156, as further described herein.

As shown in FIGS. 6-9, the distal end portion 2102 of the housing 2100defines a battery isolation protrusion aperture 2135, a needle aperture2105, a safety lock actuator groove 2133, a release member contactsurface 2126, a release member aperture 2154, a base protrusion groove2132, base retention recesses 2134A, 2134B, base rail grooves 2114, anda safety lock retention recess 2134C. The battery isolation protrusionaperture 2135 receives a battery isolation protrusion 2197 of the cover2190 (see e.g., FIG. 39) when the cover 2190 is disposed about at leasta portion of the housing 2100. The needle aperture 2105 is the openingthrough which a needle 2360 of the medicament delivery mechanism 2300and/or a needle sheath 2810 can extend (see e.g., FIGS. 8, 46-51), asdescribed in further detail herein.

The safety lock actuator groove 2133 receives an actuator 2724 of thesafety lock 2700 (see e.g., FIGS. 6 and 8 and FIGS. 40 and 41). Asdescribed in more detail herein, the actuator 2724 of the safety lock2700 is configured to move within the safety lock groove 2133 to engageand/or activate a portion of the electronic circuit system 2900 when thesafety lock 2700 is moved with respect to the housing 2100. The releasemember contact surface 2126 defines the release member aperture 2154. Asshown in FIG. 12 and as described in further detail herein, the releasemember aperture 2154 receives a distal end portion 2552 of a releasemember 2550 included in the system actuation assembly 2500. Moreover, asafety lock protrusion 2702 (see e.g., FIGS. 40-43) is disposed withinan opening 2556 between extensions 2553 of the release member 2550 (seee.g., FIG. 18) such that an engagement surface 2554 of the extensions2553 is engaged with the release member contact surface 2126 to preventactivation of the delivery device 2000. The safety lock 2700, itscomponents, and its functions are described in more detail below.

The distal base retention recesses 2134A are each configured to receivea different base connection knobs 2518 of the base 2510 (also referredto herein as “actuator,” see e.g., FIG. 16) when the base 2510 is in afirst position relative to the housing 2100. The proximal base retentionrecesses 2134B are configured to receive the base connection knobs 2518of the base 2510 when the base 2510 is in a second position relative tothe housing 2100. The base retention recesses 2134A, 2134B have atapered proximal sidewall and a non-tapered distal sidewall. Thus, thebase retention recesses 2134A, 2134B can receive the base connectionknobs 2518 to allow the base 2510 to move proximally relative to thehousing 2100, but substantially limit a distal movement of the baserelative to the housing 2100. Said another way, the distal baseretention recesses 2134A are configured to prevent the base 2510 frommoving distally when the base 2510 is in a first position and theproximal base retention recesses 2134B are configured to prevent thebase 2510 from moving distally when the base 2510 is in a secondposition. Similarly stated, the proximal base retention recesses 2134Band the base connection knobs 2518 cooperatively to limit movement ofthe base to prevent undesirable movement of the base 2510 after thedelivery device 2000 is actuated. The proximal base retention recesses2134B and the base connection knobs 2518 also provide a visual cue tothe user that the delivery device 2000 has been used. In a similarmanner, the safety lock retention recess 2134C is configured to receivea retention protrusion 2711 (see e.g., FIGS. 40 and 42) of the safetylock 2700 to at least temporarily retain the safety lock 2700 in asubstantially fixed position relative to the housing 2100.

The base actuator groove 2132 receives an electronics actuator 2520 ofthe base 2510. As described in more detail herein, the electronicsactuator 2520 of the base 2510 is configured to engage the electroniccircuit system 2900 when the base 2510 is moved with respect to thehousing 2100. The base rail grooves 2114 receive the guide members 2517of the base 2510 (see FIG. 16). The guide members 2517 of the base 2510and the base rail grooves 2114 of the housing 2100 engage each other ina way that allows the guide members 2517 of the base 2510 to slide in aproximal and/or distal direction within the base rail grooves 2114 whilelimiting lateral movement of the guide members 2517. This arrangementallows the base 2510 to move in a proximal and/or distal direction withrespect to the housing 2100 but prevents the base 2510 from moving in alateral direction with respect to the housing 2100.

As shown in FIGS. 11 and 12, the housing 2100 defines an electroniccircuit system cavity 2137 (also referred to herein as “electronicscavity”), a medicament cavity 2139, and a gas cavity 2151. Theelectronic circuit system cavity 2137 receives and/or houses theelectronic circuit system 2900. The housing 2100 has protrusions 2136(see e.g., FIG. 9) configured to stabilize the electronic circuit system2900 when disposed within the electronics cavity 2137. An outer surfaceof the housing 2100 is configured to receive a set of connectionprotrusions 2174A and connection protrusion 2174B of the electroniccircuit system 2900 (see e.g., FIG. 32). In this manner, the electroniccircuit system 2900 can be coupled to the housing 2100 within theelectronics cavity 2137. In other embodiments, the electronic circuitsystem 2900 can be coupled to the housing 2100 and disposed within theelectronics cavity 2137 by other suitable means such as an adhesive, aclip, a label and/or the like.

The electronics cavity 2137 is fluidically and/or physically isolatedfrom the gas cavity 2151 and/or the medicament cavity 2139 by a sidewall2150. The sidewall 2150 can be any suitable structure to isolate theelectronics cavity 2137 within the housing 2100 from the gas cavity 2151and/or the medicament cavity 2139 within the housing 2100. Morespecifically, the sidewall 2150 defines at least a portion of theelectronics cavity 2137 and the medicament cavity 2139, as shown in FIG.11. Furthermore, the proximal end portion 2101 of the housing 2100 iscoupled to the proximal cap 2103 such that a substantially fluid tightseal is defined therebetween. Thus, the arrangement of the sidewall 2150of the housing 2100, the proximal end portion 2101 of the housing 2100,and the proximal cap 2103 physically and/or fluidically isolates theelectronics cavity 2137 from the medicament cavity 2139 and/or the gascavity 2151. In this manner, the electronics cavity 2137 can, along withother aspects of the device 2000, produce the desired acousticperformance, as described in U.S. Pat. No. 8,021,344, entitled“Medicament Delivery Device Configured to Produce an Audible Output,”which is incorporated herein by reference in its entirety. In otherembodiments, the electronics cavity 2137 can be fluidically and/orphysically isolated from the gas cavity 2151 and the medicament cavity2139 by any suitable means. In yet other embodiments, the electronicscavity 2137 need not be physically and/or fluidically isolated from themedicament cavity 2139 and/or the gas cavity 2151.

The medicament cavity 2139 receives and/or houses the medicamentcontainer 2200 and at least a portion of the medicament deliverymechanism 2300. In particular, as described below, the medicamentdelivery mechanism 2300 includes a carrier 2370 and movable member 2330movably disposed in the medicament cavity 2139. At least a portion ofthe medicament cavity 2139 is separated from the gas cavity 2151 by asidewall 2155. Said another way, the sidewall 2155 defines at least aportion of the medicament cavity 2139 and the gas cavity 2151, as shownin FIG. 11. The arrangement of the sidewall 2155, the proximal endportion 2101 of the housing 2100, and the proximal cap 2103 is such thatat least a portion of the medicament cavity 2139 is in fluidcommunication with the gas cavity 2151 via the gas passageway 2156defined by the proximal cap 2103 (see e.g., FIG. 10), as described infurther detail herein. Moreover, the medicament cavity 2139 is open to aregion substantially outside of the housing 2100 via a needle aperture2105 (see e.g., FIGS. 11 and 12) and/or the status windows 2130, 2160.

The gas cavity 2151 has a proximal end portion 2152 and a distal endportion 2153. The gas cavity 2151 is configured to receive an energystorage member 2410 such as, for example, a device containing acompressed gas and a portion of the system actuator assembly 2500 (e.g.,a release member 2550 and a spring 2576, see e.g., FIGS. 13-15 and FIG.18), as described in further detail herein. The proximal end portion2152 of the gas cavity 2151 receives and/or houses a retention member2580 included in and/or extending from a proximal cap 2103 of thehousing 2100. As described above, the gas cavity 2151 is in fluidcommunication with the medicament cavity 2139 via the gas passageway2156. The gas cavity 2151 is open to a region substantially outside ofthe housing 2100 via a release member aperture 2154 (see e.g., FIGS. 11and 12).

FIGS. 13-26 show the system actuator assembly 2500, the medicamentdelivery mechanism 2300, and the medicament container 2200 of thedelivery device 2000. The system actuator assembly 2500 includes theenergy storage member 2410 (i.e., the gas container 2410), the base2510, a release member 2550, and a spring 2576. As shown in FIGS. 13 and14, the gas container 2410 is coupled to the proximal cap 2103 of thehousing 2100 via the retention member 2580. For example, in someembodiments, the retention member 2580 can include one or more surfacesthat have a shape associated with a contour of the gas container 2410.In this manner, the gas container 2410 can be positioned within theretention member 2580 such that the one or more surfaces selectivelyengage the gas container 2410, thereby at least temporarily maintainingthe gas container 2410 in a fixed position relative to the proximal cap2103. Moreover, when the proximal cap 2103 is coupled to the proximalend portion 2101 of the housing 2100, the gas container 2410 is disposedwithin the gas cavity 2151, as described in detail above.

The gas container 2410 includes a distal end portion 2411 and a proximalend portion 2412, and defines an inner volume that contains apressurized gas (e.g., prior to actuation). The distal end portion 2411of the gas container 2410 includes and/or defines a frangible seal 2413that can be transitioned between a first, substantially sealedconfiguration and a second, substantially open configuration. Forexample, the release member 2550 of the system actuator assembly 2500can be moved within the gas cavity 2151 and into contact with thefrangible seal 2413 to transition the frangible seal 2413 from its firstconfiguration to its second configuration, as described in furtherdetail herein. Furthermore, the length of the retention member 2580 andthe length of the release member 2550 collectively define a distancebetween a proximal end portion 2551 of the release member 2550 and thefrangible seal 2413 of the gas container 2410 when the delivery device2000 is in the storage configuration. Accordingly, this distance, whichis the distance through which the release member 2550 travels when thedelivery device 2000 is actuated, can be adjusted by changing the lengthof the retention member 2580 and/or the length of the release member2550. In some embodiments, the actuation time and/or the force exertedby the release member to, for example, puncture the frangible seal 2413can be adjusted by changing the distance between the proximal endportion 2551 of the release member 2550 and the frangible seal 2413.

As described above, the gas container 2410 is configured to contain apressurized gas prior to the frangible seal 2413 being transitioned tothe second configuration. The gas contained within the gas container2410 can be stored with any suitable pressure. Similarly, the innervolume defined by the gas container 2410, within which the pressurizedgas is disposed), can be any suitable volume. For example, in someembodiments, the inner volume can be about 0.0625 cubic inches (in³). Inother embodiments, the inner volume of the gas container 2410 can beless than about 0.0625 in³ or greater than about 0.0625 in³. In someembodiments, the gas container 2410 can contain and/or store thepressurized gas (e.g., prior to actuation of the gas container 2410) atany suitable pressure, such as a pressure of about 900 pounds per squareinch (psi), about 1000 psi, or about 1100 psi. More specifically, inthis embodiment, the gas container 2410 can store the pressurized gas atabout 1100 psi at a temperature of about 70 degrees Fahrenheit.

As described above, the arrangement of the housing 2100 can be such thatportions thereof define a substantially sealed fluid flow path throughwhich gas can flow from the gas container 2410 to a portion of themedicament cavity 2139. The pressure within the portion of the housing2100 defining the fluid flow path is substantially equal to atmosphericpressure (e.g., about 14.7 psi) prior to the actuation of the gascontainer 2410. In addition, the fluid flow path defined by the housing2100 can have a volume that is much greater than the volume defined bythe gas container 2410. For example, in this embodiment, the volume ofthe fluid flow path can be about 0.5 in³, prior to the actuation of thegas container 2410. Thus, when the gas container 2410 is transitioned toan actuated state or the like (e.g., when the frangible seal 2413 istransitioned to its second, open configuration), the compressed gasflows from the gas container 2410 having a volume of about 0.0625 in³and a pressure of about 1100 psi into the volume (e.g., the fluid flowpath) defined by the portion of the housing 2100 having the largervolume of about 0.5 in³ and the lower pressure of about one atmosphere(e.g., about 14.7 psi). Thus, the gas expands as it enters thesubstantially sealed fluid flow path defined by the portion of thehousing 2100. The expansion of the gas, in turn, increases the pressurewithin the fluid flow path defined by the portion of the housing 2100and as a result, exerts a force on the movable member 2330 to move themovable member 2330 within the medicament cavity 2139 from a first,proximal position to a second, distal position, as described in furtherdetail herein.

As shown in FIGS. 13-16, the base 2510 of the system actuation assembly2500 includes the base connection knobs 2518 and has a proximal surface2511 and a distal surface 2523. The base connection knobs 2518 engagethe base retention recesses 2134A, 2134B in a way that allows proximalmovement of the base 2510 but limits distal movement of the base 2510,as described above. The distal surface 2523 is configured to be placedin contact with a patient to actuate the delivery device 2000. Theproximal surface 2511 of the base 2510 includes an electronics actuator2520, guide members 2517 and protrusions 2515. The electronics actuator2520 is configured to engage a portion of the electronic circuit system2900, as described in further detail herein. The guide members 2517 ofthe base 2510 engage and/or slide within the base rail grooves 2114 ofthe housing 2100, as described above. The protrusions 2515 of the base2510 engage the tapered surfaces 2557 of the extensions 2553 of therelease member 2550 when the base 2510 is moved in a proximal directionrelative to the housing 2100 and/or the release member 2550. By way ofexample, when the safety lock 2700 is removed and the base 2510 is movedin a proximal direction with respect to the housing 2100, theprotrusions 2515 of the base 2510 are placed in contact with abifurcated portion of the release member 2550 in such a way that eachside is brought closer to the other, thereby actuating the deliverydevice 2300, as described in further detail herein.

The base 2510 defines a needle aperture 2513, a safety lock protrusionaperture 2514, a battery isolation protrusion aperture 2521, a safetylock actuator opening 2524, and pull-tab openings 2519 (see e.g., FIGS.14-16). As described in further detail herein, the needle aperture 2513receives the needle 2360 when the delivery device 2000 is actuated; thesafety lock protrusion aperture 2514 receives a safety lock protrusion2702 of the safety lock 2700 when the safety lock 2700 is coupled to thehousing 2100 and/or the base 2510 (see e.g., FIG. 13); the batteryisolation protrusion aperture 2521 receives a battery isolationprotrusion 2197 of the cover 2190 and a stopper 2727 of the safety lock2700; the safety lock actuator opening 2524 receives a safety lockactuator 2724 of the safety lock 2700; and the pull-tab openings 2519receive pull-tabs 2710 of the safety lock 2700.

FIG. 17 shows certain components of the system actuation assembly 2500,the medicament delivery mechanism 2300, and the medicament container2200 without the base 2510 and the spring 2576 so that the releasemember 2550 can be more clearly shown. The release member 2550 ismovably disposed within the distal end portion 2153 of the gas cavity2151. The release member 2550 has the proximal end portion 2551 and adistal end portion 2552. The proximal end portion 2551 includes a sealmember 2574 and a puncturer 2575. The release member 2550 is disposedwithin the gas cavity 2151 in such a manner that the seal member 2574engages an inner surface of the housing 2100 that defines at least aportion of the gas cavity 2151 (e.g., the sidewall 2155 and/or any otherwall of the housing 2100 defining the gas cavity 2151). Morespecifically, the seal member 2574 is in contact with the inner surfaceof the housing 2100 that defines the gas cavity 2151 to form and/ordefine a substantially fluid tight seal therebetween. Thus, the proximalend portion 2152 of the gas cavity 2151 is fluidically isolated from thedistal end portion 2153 of the gas cavity 2151 via the fluidic sealdefined between the inner surface of the housing 2100 and the sealmember 2574.

The puncturer 2575 of the proximal end portion 2551 of the releasemember 2550 is configured to contact and puncture the frangible seal2413 on the gas container 2410 when the release member 2550 movesproximally within the gas cavity 2151, as shown by the arrow DD in FIG.17. In this manner, when gas is released from the gas container 2410,the seal member 2574 substantially prevents the gas contained in theproximal end portion 2152 of the gas cavity 2151 from entering thedistal end portion 2153 of the gas cavity 2151. As described above andin further detail herein, a pressure within the gas cavity 2151 is lowerthan the pressure within the gas container 2410, prior to the frangibleseal 2413 being punctured, and a volume defined by at least a portion ofthe gas cavity 2151 is larger than the volume defined by the gascontainer 2410. Thus, upon puncturing the frangible seal 2413, the gasescapes the gas container 2410 and expands within the gas cavity 2151,thereby exerting a force on the release member 2550. In some instances,the force exerted on the release member 2550 can be sufficient to movethe release member 2550 in the distal direction (e.g., opposite thearrow DD in FIG. 17), which in turn, compresses the spring 2576 disposedabout a portion of the release member 2550 (see e.g., FIGS. 13 and 14).In some such instances, the force exerted by the expansion of the gascan be sufficient to compress the spring 2576 to a substantially solidconfiguration (e.g., completely compressed). As such, the spring 2576and the release member 2550 can act, for example, as an accumulator orthe like based at least in part on a force exerted by the expansion ofthe gas as it leaves the gas container 2410, as described in furtherdetail herein.

The distal end portion 2552 of the release member 2550 includesextensions 2553. As described above, the extensions 2553 can form, forexample, a bifurcated portion of the release member 2550. Each extension2553 includes a projection 2555 with a tapered surface 2557 and anengagement surface 2554. Further, the extensions 2553 define an opening2556 therebetween. The projections 2555 are configured to extend throughthe release member aperture 2154 of the housing 2100 in such a mannerthat the engagement surfaces 2554 are placed in contact the releasemember contact surface 2126 of the housing 2100, as shown in FIG. 18. Inthis manner, the engagement surfaces 2554 of the projections 2555 limitproximal movement of the release member 2550 when the engagementsurfaces 2554 are in contact with the release member contact surface2126 of the housing 2100.

The opening 2556 defined by the extensions 2553 receives the safety lockprotrusion 2702 of the safety lock 2700 (see e.g., FIGS. 18 and 40-43)when the safety lock 2700 is coupled to the housing 2100 and/or the base2510. With the safety lock protrusion 2702 disposed between theextensions 2553, radial (or inward) movement of the extensions 2553towards each other is limited and/or substantially prevented. Saidanother way, the safety lock protrusion 2702 is configured to ensurethat the extensions 2553 remain spaced apart and the engagement surfaces2554 of the projections 2555 remain in contact with the release membercontact surface 2126 of the housing 2100. Moreover, as shown in FIG. 18,the system actuation assembly 2500 and the housing 2100 is such that thespring 2576 is disposed between the proximal end portion 2551 of therelease member 2550 (e.g., a flange, a surface, and/or the like includedin the proximal end portion 2551) and a surface of the housing 2100 thatdefines a distal surface of the gas cavity 2151. Thus, with theengagement surface 2554 of each extension 2553 in contact with therelease member contact surface 2126 of the housing 2100, the spring 2576is maintained in a configuration having, for example, a relatively highpotential energy (e.g., in a compressed configuration). In this manner,the engagement surface 2554 of each extension 2553 contacts the releasemember contact surface 2126 and in turn, exerts a reaction force inresponse to a force exerted by the spring 2576 associated with theconfiguration of relatively high potential energy. As such, thepuncturer 2575 can be at least temporarily retained in a position withinthe gas cavity 2151 that is spaced apart from the gas container 2410. Insome embodiments, for example, the release member 2550 and/or theextensions 2553 can be constructed from any suitable material configuredto withstand deformation that may occur when exposed to a load over anextended period of time (e.g., exerted by and/or otherwise associatedwith the spring 2576 in the configuration having relatively highpotential energy). In some embodiments, for example, the release member2550 and/or the extensions 2553 can be constructed from and/or include asurface constructed from brass or the like. Thus, the release member2550 and/or the extensions 2553 can have a stiffness and/or hardnesssufficient to withstand fatigue associated with the force exerted by thespring 2576.

The tapered surfaces 2557 of the projections 2555 are configured tocontact tapered surfaces 2522 of contact protrusions 2515 extending fromthe proximal surface 2511 of the base 2510, as shown in FIG. 18.Accordingly, when the base 2510 is moved proximally relative to thehousing 2100, the extensions 2553 are moved together by the taperedsurfaces 2522 of the contact protrusions 2515. The inward movement ofthe extensions 2553 causes the release member 2550 to disengage therelease member contact surface 2126 of the housing 2100, therebyallowing the release member 2550 to be moved proximally along itslongitudinal axis. More specifically, by disengaging the engagementsurface 2554 of the extensions 2553 from the release member contactsurface 2126, the reaction force exerted in response to the forceexerted by the spring 2576 is removed and thus, the spring 2576 convertsthe potential energy into kinetic energy, resulting in expansion of thespring 2576.

As shown in FIGS. 19-21, the medicament container 2200 of the deliverydevice 2000 has a body 2210 with a proximal end portion 2212 and adistal end portion 2213. The body 2210 defines a volume that contains(i.e., is filled with or partially filled with) a naloxone composition2220 such as those described herein. The distal end portion 2213 of themedicament container 2200 includes a neck 2215, a cap 2250, and a seal2251. The cap 2250, which can be, for example, an 8-I crimp seal or thelike, is fixedly coupled about a portion of the neck 2215 and includes aseal 2251. The cap 2250 is disposed about the neck 2215 of themedicament container 2200 such that the seal 2251 and, for example, adistal surface of the medicament container 2200 form a substantiallyfluid tight seal. As such, the seal 2251 can limit and/or substantiallyprevent leaching of a portion of the naloxone composition 2200 throughthe distal end portion 2213 of the medicament container 2200. Moreover,the cap 2250 can be crimped, molded, and/or otherwise disposed about themedicament container 2200 during a manufacturing process with a forcethat is sufficient to maintain the cap 2250 about the portion of themedicament container 2200 regardless of an increase in pressure withinthe medicament container 2200 in response to an injection event. Saidanother way, the cap 2250 can be fixedly coupled to the portion of themedicament container 2200 and can be maintained thereabout withsufficient force (e.g., a friction force, a force resulting from aninternal stress with the cap 2250 and/or medicament container 2200,and/or any other suitable force) to resist a decoupling of the cap 2250from the portion of the medicament container 2200 as the pressuretherein is increased during an injection event.

With the seal 2251 disposed between an inner surface of the cap 2250and, for example, a distal surface of the medicament container 2200 (seee.g., FIG. 20), a portion of the force that couples the cap 2250 to themedicament container 2200 deforms a portion of the seal 2251. Thus, insome embodiments, the seal 2251 can have a first portion (e.g., anannular portion substantially aligned with the distal surface of themedicament container 2200) having a first thickness and a second portion(e.g., a portion substantially aligned with an opening defined by thedistal surface of the medicament container 2200) having a secondthickness that is thicker than the first thickness, as shown in FIG. 20.As described in further detail herein, a distal portion of the needle2360 can have a length that is sufficient to puncture the seal 2251(e.g., the second portion of the seal 2251) in such a manner that alumen defined by the needle 2360 is substantially unobstructed by theseal 2251 and placed in fluid communication with the naloxonecomposition 2220.

The proximal end portion 2212 of the medicament container 2200 issubstantially open to receive a portion of the movable member 2330.Similarly, during a manufacturing process and/or the like, anelastomeric member 2217 (also referred to here as “plunger”) can beinserted through the open proximal end portion 2212 to be movablydisposed within the medicament container 2200. For example, the plunger2217 can be disposed in the medicament container 2200 such that thenaloxone composition is disposed between a distal surface of the plunger2217 and a proximal surface of the seal 2251 (described above). Thus,when the medicament container 2200 is assembled in the delivery device1000, a force can be exerted on the movable member 2330, which in turn,exerts a force on the plunger 2217 to move the plunger 2217 within themedicament container 2200, as described in further detail herein.

The medicament container 2200 can have any suitable size (e.g., lengthand/or diameter) and can define an inner region (e.g., between thedistal surface of the plunger 2217 disposed therein and the proximalsurface of the seal 2251) having any suitable volume, within which avolume of the naloxone composition 2220 is disposed. Moreover, themedicament container 2200 and the movable member 2330 can becollectively configured such that the movable member 2330 travels adesired distance within the medicament container 2200 (i.e., the“stroke”) during an injection event. In this manner, the medicamentcontainer 2200 can provide, for example, a desired fill volume and/or adesired delivery volume of the naloxone composition 2220. In someembodiments, for example, the size of the medicament container 2200 andthe length of the movable member 2330 can be such that the fill volumeof the naloxone composition 2220 is approximately between about 0.3milliliters (mL) and about 2 mL. In other embodiments, the fill volumeof the naloxone composition 2220 can be about 0.4 mL, about 0.5 mL,about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1 mL,about 1.25 mL, about 1.5 mL, about 1.75 mL, about 2.0 mL, or anyfraction therebetween. In at least one embodiment, the fill volume ofthe naloxone composition 2220 can be about 0.34 mL. In otherembodiments, the fill volume of the naloxone composition 2220 can beabout 0.41 mL. In still other embodiments, the fill volume of thenaloxone composition 2220 can be about 0.76 mL. In other embodiments,the fill volume of the naloxone composition 2220 can be less than about0.3 mL or greater than about 2.0 mL.

In some embodiments, the arrangement of the movable member 2330 and/orthe medicament container 2200 can be such that the delivered volume ofthe naloxone composition 2220 after an injection event (i.e., avolumetric amount delivered to a patient) is less than the fill volumeof the naloxone composition 2220. For example, in some embodiments, thedelivered volume of the naloxone composition 2220 can be between about0.3 mL and about 2.0 mL. In other embodiments, the delivered volume ofthe naloxone composition 2220 can be about 0.4 mL, about 0.5 mL, about0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1 mL, about 1.25mL, about 1.5 mL, about 1.75 mL, about 2.0 mL, or any fractiontherebetween. In some embodiments, the delivered volume of the naloxonecomposition 2220 can be between about 0.34 mL and about 0.46 mL. In atleast one embodiment, the delivered volume of the naloxone composition2220 can be about 0.34 mL. In other embodiments, the delivered volume ofthe naloxone composition 2220 can be about 0.4 mL. In still otherembodiments, the delivered volume of the naloxone composition 2220 canbe less than about 0.3 mL or greater than about 2.0 mL. In at least oneembodiment, the fill volume of the naloxone composition 2220 can beabout 0.58 mL and the delivered volume of the naloxone composition 2220can be about 0.4 mL. In some embodiments, the medicament container 2200and/or the movable member 2330 can be arranged such that a ratio of adelivered volume of the naloxone composition 2220 to a fill volume ofthe naloxone composition 2220 is about 0.1, about 0.2, about 0.3, about0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or about1.0.

Moreover, the length of the medicament container 2200 and the length ofthe movable member 2330 can be configured such that the medicamentdelivery mechanism 2300 can fit in the same housing 2100 regardless ofthe fill volume, the delivery volume and/or the ratio of the fill volumeto the delivery volume. In this manner, the same housing and productiontooling can be used to produce devices having various volumes of thenaloxone composition. For example, in a first embodiment (e.g., having afill volume to delivery volume ratio of 0.4), the medicament containerhas a first length and the movable member has a first length. In asecond embodiment (e.g., having a fill volume to delivery volume ratioof 0.6), the medicament container has a second length shorter than thefirst length, and the movable member has a second length longer than thefirst length. In this manner, the stroke of the device of the secondembodiment is longer than that of the device of the first embodiment,thereby allowing a greater volume of the naloxone composition 2220 to bedelivered. The medicament container of the device of the secondembodiment, however, is shorter than the medicament container of thedevice of the first embodiment, thereby allowing the components of bothembodiments to be disposed within the same housing and/or a housinghaving the same length.

The naloxone composition 2220 contained within the medicament container2200 can be any of the naloxone compositions described herein, and inU.S. Pat. No. 8,627,816 entitled “Medicament Delivery Device forAdministration of Opioid Antagonists Including Formulations forNaloxone,” which is incorporated herein by reference in its entirety. Inparticular, the naloxone composition 2220 can include at least aneffective dosage of naloxone or salts thereof. In some embodiments, thenaloxone composition 2220 can include an effective dosage of naloxone orsalts thereof, a tonicity-adjusting agent, pH-adjusting agent, astabilizing agent, and/or the like. The naloxone composition 2220 can beformulated such that the osmolality of the naloxone composition 2220ranges from about 250-350 mOsm and the pH ranges from about 3-5.

In some embodiments, the naloxone composition 2220 can include anysuitable concentration of 4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one. In some embodiments, for example, the naloxonecomposition 2220 has a concentration of4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one betweenapproximately 0.01 milligrams per milliliter (mg/mL) and approximately50 mg/mL. In other embodiments, the naloxone composition 2220 has aconcentration of 4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-onebetween approximately 0.05 mg/mL and approximately 2 mg/mL.

In some embodiments, the naloxone composition 2220 has a dose of4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one betweenapproximately about 0.2 mg and about 10 mg. In other embodiments, theamount of the dose can be about 0.4 mg, about 0.5 mg, about 0.6 mg,about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.25 mg,about 1.5 mg, about 1.75 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg,about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg,about 10.0 mg, or any fraction therebetween. In at least one embodiment,the amount of the dose can be about 0.4 mg. In other embodiments, theamount of the dose can be less than about 0.2 mg or greater than about10.0 mg.

The tonicity-adjusting agent can be any of the tonicity-adjusting agentsdescribed herein, and can be included within the naloxone composition2220 in any suitable amount and/or concentration. For example, in someembodiments, the tonicity-adjusting agent includes at least one ofdextrose, glycerin, mannitol, potassium chloride or sodium chloride. Inother embodiments, the tonicity-adjusting agent includes sodium chloridein an amount such that a concentration of sodium chloride is betweenapproximately 0.1 mg/mL and approximately 20 mg/mL.

The pH-adjusting agent can be any of the pH-adjusting agents describedherein, and can be included within the naloxone composition 2220 in anysuitable amount and/or concentration. For example, in some embodiments,the pH-adjusting agent includes at least one of hydrochloric acid,citric acid, citrate salts, acetic acid, acetate salts, phosphoric acidor phosphate salts. In other embodiments, the pH-adjusting agentincludes a dilute hydrochloric acid.

The elastomeric member 2217 can be of any design or formulation suitablefor contact with the naloxone composition 2220. For example, theelastomeric member 2217 can be formulated to minimize any reduction inthe efficacy of the naloxone composition 2220 that may result fromcontact (either direct or indirect) between the elastomeric member 2217and the naloxone composition 2220. For example, in some embodiments, theelastomeric member 2217 can be formulated to minimize any leaching orout-gassing of compositions that may have an undesired effect on thenaloxone composition 2220. In other embodiments, the elastomeric member2217 can be formulated to maintain its chemical stability, flexibilityand/or sealing properties when in contact (either direct or indirect)with naloxone over a long period of time (e.g., for up to six months,one year, two years, five years or longer).

In some embodiments, the elastomeric member 2217 can be formulated toinclude a polymer and a curing agent. In such embodiments, the polymercan include at least one of bromobutyl or chlorobutyl. In suchembodiments, the curing agent can include at least one of sulfur, zincor magnesium.

In some embodiments, the elastomeric member 2217 can be constructed frommultiple different materials. For example, in some embodiments, at leasta portion of the elastomeric member 2217 can be coated. Such coatingscan include, for example, polydimethylsiloxane. In some embodiments, atleast a portion of the elastomeric member 2217 can be coated withpolydimethylsiloxane in an amount of between approximately 0.02 mg/cm2and approximately 0.80 mg/cm2. In other embodiments, the elastomericmember 2217 can include multiple materials in any suitable manner, blendor composition. For example, in some embodiments, at least a portion ofthe elastomeric member 2217 can include polydimethylsiloxane in anysuitable amount (e.g., in an amount of between approximately 0.02 mg/cm2and approximately 0.80 mg/cm2.)

The medicament delivery mechanism 2300 of the delivery device 2000includes the carrier 2370, the movable member 2330, and a retractionspring 2351. As described above, the carrier 2370 and the movable member2330 are each movably disposed within the medicament cavity 2139 of thehousing 2100. In addition, the carrier 2370 movably receives at least aportion of the medicament container 2200 in such a way that allows themedicament container 2200 to move contemporaneously with the carrier2370 or relative to the carrier 2370. As shown in FIGS. 22 and 25, themovable member 2330 includes a piston rod 2333, and has a proximal endportion 2331 and a distal end portion 2332. The movable member 2330 canbe constructed of a resilient, durable, and/or sealing material orcombination of materials, such as a rubber. The distal end portion 2332of the movable member 2330 is disposed within the proximal end portion2212 of the medicament container 2200 and in contact with the plunger2217. As described in further detail herein, the movable member 2330 canbe moved within the medicament cavity 2139 to collectively move thecarrier 2370, the medicament container 2200, and the plunger 2217; tocollectively move the medicament container 2200 and the plunger 2217relative to the carrier 2370; and to move the plunger 2217 relative tothe medicament container 2200.

The proximal end portion 2331 includes a seal member 2339. The sealmember 2339 engages the sidewall of the housing 2100 to define asubstantially fluidic seal therebetween. Thus, a portion of themedicament cavity 2139 that is disposed on proximal to the seal member2339 (e.g., a gas chamber) is fluidically isolated from a portion of themedicament cavity 2139 that is disposed on distal to the seal member2339. Moreover, the portion of the medicament cavity 2139 disposedproximal to the seal member 2339 is in fluid communication with theportion of the gas cavity 2151 that is proximal to the seal member 2574of the release member 2550 via the gas passageway 2151, as described indetail above. The proximal end portion 2331 and/or the seal member 2339also includes a gas relief valve 2340 (see e.g., FIG. 25) that can beselectively actuated to allow fluid communication between the portion ofthe medicament cavity 2139 proximal to the seal member 2339 and theportion the portion of the medicament cavity 2139 distal to the sealmember 2339. As described in more detail below, the gas relief valve2340 allows a gas pressure within the gas chamber to be reduced uponcompletion of the injection event.

As shown in FIGS. 21-26, the carrier 2370 includes a proximal endportion 2371, a distal end portion 2372, a first side portion 2373, asecond side portion 2374, and a locking protrusion (or leg) 2387. Thedistal end portion 2372 forms a cup or the like (see e.g., FIGS. 24 and25). That is to say, the distal end portion 2372 can include asubstantially annular wall (or set of walls) that extends a distancefrom a distal surface of the carrier 2370. In this manner, the distalend portion 2372 has an inner surface 2375 that substantiallycircumscribes a volume configured to receive, for example, the distalend portion 2213 of the medicament container 2200. The inner surface2375 includes a ribbed portion 2376 that is configured to selectivelyengage the distal end portion 2213 of the medicament container 2200 (seee.g., FIG. 25). For example, the ribbed portion 2376 of the innersurface 2375 can contact the medicament container 2200 to define and/orform a “snap-fit” connection that can allow the medicament container2200 to be selectively moved relative to the carrier 2370 between afirst position and a second position during an injection event. In thefirst position (e.g., a proximal position), the carrier 2370 can bemoved within the medicament cavity 2139 such that movement of thecarrier 2370 within the medicament cavity 2139 results incontemporaneous movement of the medicament container 2200 within themedicament cavity 2139. More specifically, the ribbed portion 2376 is incontact with, for example, a distal surface of the medicament container2200 in such a manner that at least temporarily retains the medicamentcontainer 2200 in a substantially fixed position relative to the carrier2370. Thus, the carrier 2370 and the medicament container 2200 are movedconcurrently.

When the carrier 2370 and the medicament container 2200 are moved to thesecond position (e.g., a distal position), a force can be exerted on aportion of the carrier 2370 that can limit and/or otherwisesubstantially prevent further movement (e.g., distal movement) of thecarrier 2370 and thus, the carrier 2370 is at least temporarilymaintained in its second position. The force, however, is not exerted onthe medicament container 2200 and as a result, in the presence of thegas pressure on the movable member 2300, the medicament container 2200is moved relative to the carrier 2370. As the distal end portion 2213 ofthe medicament container 2200 moves along the inner surface 2375, thedistal end portion 2213 of the medicament container 2200 is, forexample, released from the snap-fit, thereby allowing the medicamentcontainer 2200 to move relative to the carrier 2370 (e.g., in the distaldirection).

As shown in FIGS. 22-25, the distal end portion 2372 of the carrier 2370is coupled to the needle 2360. More specifically, the distal end portion2372 defines an opening 2377 through which the needle 2360 extends suchthat a proximal end portion 2361 of the needle 2360 is disposed withinthe volume that is circumscribed by the annular wall of the distal endportion 2372. In some embodiments, the needle 2360 can be fixedlycoupled to the carrier 2370 via an adhesive 2365 or the like, as shownin FIGS. 24 and 25. The arrangement of the carrier 2370, the needle2360, and the medicament container 2200 can be such that the proximalend portion 2361 of the needle 2360 is spaced apart from the seal 2251of the medicament container 2200 (see e.g., FIG. 25) when the carrier2370 and the medicament container 2200 are collectively in the firstposition (e.g., prior to an injection event). When the medicamentcontainer 2200 is moved relative to the carrier 2370 (e.g., when thecarrier 2370 is its second position during the injection event), theproximal end portion 2361 of the needle 2360 pierces the seal 2251 suchthat substantially an entire proximal surface of the needle 2360 is in aproximal position relative to the seal 2251. In this manner, a lumen2364 of the needle 2360 can be selectively placed in fluid communicationwith the medicament container 2200 to define a medicament delivery paththrough which the naloxone composition 2220 can flow. Moreover, theneedle 2360 can be any suitable size or gauge (e.g., 18 gauge, 24 gauge,27 gauge, 32 gauge, etc.) to deliver the naloxone composition 2220through the lumen 2364 and into the body of the patient with a desiredset of pharmacokinetic characteristics, as described in further detailherein.

The first side portion 2373 and the second side portion 2374 of thecarrier 2370 extend from the distal end portion 2372 to the proximal endportion 2371. Moreover, the first side portion 2373 and the second sideportion 2374 from a bifurcated region of the carrier 2370, as shown inFIGS. 21-23. This arrangement allows at least the distal end portion2213 of the medicament container 2200 to be disposed within (and/orremoved from) the carrier 2370. In some embodiments, the first sideportion 2373 and the second side portion 2374 can define a distancetherebetween that is slightly smaller than a diameter of the medicamentcontainer 2200 and thus, when the medicament container 2200 is disposedwithin the carrier 2370, the first side portion 2373 and the second sideportion 2374 can exert a substantially lateral force on a surface of themedicament container 2200 that is sufficient to maintain the medicamentcontainer 2200 within the carrier 2370, while allowing the medicamentcontainer 2200 to move relative to the carrier 2370, as described above.The bifurcated arrangement of the carrier 2370 also allows at least aportion of the medicament container 2200 to be visible via the statuswindows 2130, 2160 of the housing (substantially unobstructed by thecarrier 2370).

The proximal end portion 2371 of the carrier 2370 includes a gas valveactuator 2380 and a retraction spring protrusion 2382. Morespecifically, as shown in FIGS. 21-23, the second side 2374 of thecarrier 2370 includes a shoulder 2378 having a proximal surface fromwhich the gas valve actuator 2380 extends, and a distal surface fromwhich the retraction spring protrusion 2382 extends. The gas valveactuator 2380 is configured to engage a gas relief valve 2340 of themovable member 2330 to allow the pressurized gas contained within thegas chamber (i.e., the volume within the medicament cavity 2139 betweenthe proximal end of the housing 2100 and the proximal end of the movablemember 2330) to escape when the injection event is complete.

The retraction spring protrusion 2382 extends from the distal surface ofthe shoulder 2378 to engage the retraction spring 2351. Moreparticularly, a portion of the retraction spring 2351 is disposed aboutthe retraction spring protrusion 2382. In other embodiments, theretraction spring protrusion 2382 can include any suitable features forengaging and/or retaining the retraction spring 2351 (e.g., a recess orthe like). In this manner, the retraction spring 2351 can be disposedbetween the shoulder 2378 of the carrier 2370 and a distal surface ofthe housing 2100 and can be transitioned from a first configurationhaving a first potential energy to a second configuration having asecond, higher potential energy. Moreover, when the retraction spring2351 is placed in its second configuration and the gas valve actuator2380 engages the gas relief valve 2340 of the movable member 2330, a gaspressure within the medicament cavity 2139 can be decreased below athreshold, such that the force exerted by the retraction spring 2351 onthe carrier 2370 (e.g., as a result of being placed in its secondconfiguration) is sufficient to move the carrier 2370 in a proximaldirection within the housing 2100 (i.e., to retract), as described infurther detail herein. In addition, this arrangement results in therebeing substantially no residual force within the housing, whichdecreases stress on the components after the injection event.

As described above, the carrier 2370 includes a locking leg 2387 thatextends from the distal end portion 2372 towards the proximal endportion 2371. The locking leg 2387 can be a relatively flexibleextension or the like that can selectively bend, flex, deform (e.g.,elastic deformation or plastic deformation), and/or otherwisereconfigure between a first configuration and a second configuration.For example, as shown in FIGS. 22 and 23, the locking leg 2387 extendsfrom the second side portion 2374 of the carrier 2370 at angle. As such,in some instances, a force can be exerted the locking leg 2387 that canincrease or decrease the angle.

The locking leg 2387 includes a protrusion 2388 that is selectivelydisposed in a retraction lock aperture 2162 defined by a sidewall of thehousing 2100 defining a portion of the medicament cavity 2139 (see e.g.,FIG. 26) when the carrier 2370 and the medicament container 2200 are inthe first (i.e., storage) position. More specifically, the protrusion2388 is in contact with a surface of the housing 2100 defining and/orotherwise bounding the retraction lock aperture 2162 in the proximaldirection. This arrangement limits movement of the carrier 2370 and themedicament container 2200 in the proximal direction. In this manner, theretraction spring 2351 can be preloaded with a desired amount forceprior to an injection event (e.g., during a manufacturing process).Thus, when the retraction spring 2351 is in contact with the shoulder2378 of the carrier 2370 (e.g., disposed about the retraction springprotrusion 2382), a force exerted by the retraction spring 2351 inresponse to the preload is offset by a reaction force in the oppositedirection exerted by the proximal surface of the housing 2100 definingthe portion of the retraction lock aperture 2162 on the protrusion 2388of the locking leg 2387.

In some instances, the arrangement of the medicament container 2200and/or the movable member 2300 can be such that an amount of preloadedforce in the retraction spring 2351 is varied. For example, in someinstances, the length of the piston rod 2333 of the movable member 2330and/or a length of the medicament container 2200 can be increased ordecreased based at least in part on a volume of the naloxone composition2220 disposed in the medicament container 2200 and/or the desireddelivery volume. In some embodiments, such a change can result in achange in the initial position of the movable member 2330, the carrier2370, and/or the medicament container 2200 relative to the housing 2100.This, in turn, can result in a change in the preloaded force in theretraction spring 2351 and/or an increase or decrease in a distance ofretraction, a point during an injection event in which the retractionspring 2351 is actuated, and/or the like. Thus, regardless of the amountof preloaded force in the retraction spring 2351 corresponding thearrangement of the medicament delivery mechanism 2300 and the medicamentcontainer 2200, the protrusion 2388 of the locking leg 2387 can engagethe proximal surface of the housing 2100 to substantially prevent aproximal movement of the medicament delivery mechanism 2300 and/or themedicament container 2200. This arrangement also limits proximal motionof the medicament delivery mechanism 2300 during assembly (e.g., whenthe needle sheath 2810 is being pressed about the needle 2360).

FIGS. 27-36 show the electronic circuit system 2900 of the deliverydevice 2000. The electronic circuit system 2900 includes an electroniccircuit system housing 2170, a printed circuit board 2922, a batteryassembly 2962, an audio output device 2956, two light emitting diodes(LEDs) 2958A, 2958B, and a battery clip 2910. As shown in FIG. 34, theelectronic circuit system 2900 is disposed within the electronic circuitsystem cavity 2137 of the housing 2100. As described herein, theelectronic circuit system 2900 is configured to output an electronicoutput associated with the use of the delivery device 2000.

As shown in FIGS. 27-29, the electronic circuit system housing 2170 ofthe electronic circuit system 2900 includes a distal end portion 2172and a proximal end portion 2171. The proximal end portion 2171 of theelectronic circuit system housing 2170 defines multiple sound apertures2173. The audible output device 2956 is disposed against the proximalend portion 2171 of the electronic circuit system housing 2170 such thatthe front face of the audible output device 2956 is disposed adjacentthe sound apertures 2173. In this manner, the sound apertures 2173 canallow sound produced by the audio output device 2956 to pass from theaudio output device 2956 to a region outside of the housing 2100.

The proximal end portion 2171 also includes connection protrusions 2174Aand a battery clip protrusion 2176 (see e.g., FIG. 29). The connectionprotrusions 2174A are configured to matingly engage a surface of thesidewalls of the housing 2100 that define the electronic cavity 2137, asdescribed above. In this manner, the electronic circuit system 2900 canbe coupled to the housing 2100 and at least partially disposed withinthe electronic circuit system cavity 2137. In other embodiments, theelectronic circuit system 2900 can be coupled to the housing 2100 byother suitable means such as an adhesive, a clip, a label and/or thelike. As described in more detail herein, the battery clip protrusion2176 is configured to hold the battery clip 2910 in place.

As shown in FIGS. 27-29, the distal end portion 2172 of the electroniccircuit system housing 2170 includes the connection protrusion 2174B, astiffening protrusion 2177 and defines an LED aperture 2178, apertures2175, a safety lock actuator groove 2179 and a base actuator groove2180. The LED aperture 2178 is configured to receive the LEDs 2958A,2958B such that a user can view the LEDs 2958A, 2958B, which aredescribed in more detail herein. The connection protrusion 2174B extendsfrom the distal end portion 2172 of the electronic circuit systemhousing 2170, and is configured to attach the electronic circuit system2900 to the housing 2100, as described above. The stiffening protrusion2177 is configured to engage a portion of the housing 2100 (e.g., aprotrusion, tab, and/or the like) that can be accessible via theapertures 2175. The stiffening protrusion 2177 is configured to limitbending (e.g., buckling) of the electronic circuit system housing 2170when the electronic circuit system housing 2170 is coupled to thehousing 2100. Moreover, the stiffening protrusion 2177 can be disengagedfrom the portion of the housing 2100 via the apertures 2175.

As shown in FIG. 29, the safety lock actuator groove 2179 of theelectronic circuit system housing 2170 is configured to be disposedadjacent the safety lock actuator groove 2133 of the distal end portion2102 of the housing 2100. In this manner, the safety lock actuatorgroove 2179 of the electronic circuit system housing 2170 and the safetylock actuator groove 2133 of the distal end portion 2102 of the housing2100 collectively receive the electronic circuit system actuator 2724(also referred to simply as the “actuator” 2724) of the safety lock2700, which is described in more detail herein. Similarly, the baseactuator groove 2180 of the electronic circuit system housing 2170 isconfigured to be disposed adjacent the base actuator groove 2132 of thedistal end portion 2102 of the housing 2100. The base actuator groove2180 of the electronic circuit system housing 2170 and the base actuatorgroove 2132 of the distal end portion 2102 of the housing 2100collectively receive the electronics actuator 2520 of the base 2510,which is described in more detail herein.

The battery assembly 2962 of the electronic circuit system 2900 includestwo batteries stacked on top of one another. In other embodiments, theelectronic circuit system can include any number of batteries and/or anysuitable type of power source. In some embodiments, for example, thebattery assembly can include Lithium batteries such as, for example,CR1616, CR2016s, type AAA or the like. The battery assembly 2962 has afirst surface 2964 and a second surface 2966. The first surface 2964 ofthe battery assembly 2962 can contact an electrical contact (not shown)disposed on the substrate 2924. The second surface 2966 of the batteryassembly 2962 is configured to contact a contact portion 2918 of adistal end portion 2916 of a battery clip 2910. When both the electricalcontact of the substrate 2924 and the contact portion 2918 of the distalend portion 2916 of the battery clip 2910 contact the battery assembly2962, the batteries of the battery assembly 2962 are placed inelectrical communication with the electronic circuit system 2900. Saidanother way, when the electrical contact of the substrate 2924 and thecontact portion 2918 of the distal end portion 2916 of the battery clip2910 contact the battery assembly 2962, the battery assembly 2962 isconfigured to supply power to the electronic circuit system 2900.

The battery clip 2910 (shown in FIGS. 28 and 30) includes a proximal endportion 2912 and a distal end portion 2916. The proximal end portion2912 defines a retention aperture 2913. The retention aperture 2913 isconfigured to receive a screw 2911 to couple the battery clip 2910 tothe battery clip protrusion 2176 of the electronic circuit systemhousing 2170. In this manner, the battery clip protrusion 2176 maintainsthe position of the battery clip 2910 with respect to the electroniccircuit system housing 2170 and/or the battery assembly 2962.

The distal end portion 2916 of the battery clip 2910 includes a contactportion 2918 and an angled portion 2917. The contact portion 2918 isconfigured to contact the second surface 2966 of the battery assembly2962 to place the battery assembly 2962 in electrical communication withthe electronic circuit system 2900. The angled portion 2917 of thedistal end portion 2916 of the battery clip 2910 is configured to allowa proximal end portion 2236 of a battery isolation protrusion 2197 (seee.g., FIG. 38) to be disposed between the second surface 2966 of thebattery assembly 2962 and the contact portion 2918 of the distal endportion 2916 of the battery clip 2910. When the battery isolationprotrusion 2197 is disposed between the second surface 2966 of thebattery assembly 2962 and the contact portion 2918 of the distal endportion 2916 of the battery clip 2910, the electrical path between thebattery assembly 2962 and the remainder of the electrical circuit system2900 is disrupted, thereby removing power from the electronic circuitsystem 2900. The contact portion 2918 of the distal end portion 2916 ofthe battery clip 2910 is biased such that when the battery isolationprotrusion 2197 is removed, the contact portion 2918 will move intocontact the second surface 2966 of the battery assembly 2962, therebyrestoring electrical communication between the battery assembly 2962 andthe electronic circuit system 2900. In some embodiments, the batteryisolation protrusion 2197 can be repeatedly removed from between thesecond surface 2966 of the battery assembly 2962 and the contact portion2918 of the distal end portion 2916 of the battery clip 2910 andreinserted. Said another way, the battery isolation protrusion 2197 andthe battery clip 2910 collectively form a reversible on/off switch.

The audio output device 2956 of the electronic circuit system 2900 isconfigured to output audible sound to a user in response to use of thedelivery device 2000. In some embodiments, the audible output device2956 can be a speaker. In some embodiments, the audible sound can be,for example, associated with a recorded message and/or a recordedspeech. In other embodiments, the audible instructions can be an audiblebeep, a series of tones and/or or the like.

In some embodiments, the delivery device 2000 can have a networkinterface device (not shown) configured to operatively connect theelectronic circuit system 2900 to a remote device (not shown) and/or acommunications network (not shown). In this manner, the electroniccircuit system 2900 can send information to and/or receive informationfrom the remote device. The remote device can be, for example, a remotecommunications network, a computer, a compliance monitoring device, acell phone, a personal digital assistant (PDA) or the like. Such anarrangement can be used, for example, to download replacementprocessor-readable code from a central network to the electronic circuitsystem 2900. In some embodiments, for example, the electronic circuitsystem 2900 can download information associated with a delivery device2000, such as an expiration date, a recall notice, updated useinstructions or the like. Similarly, in some embodiments, the electroniccircuit system 2900 can upload information associated with the use ofthe delivery device 2000 via the network interface device (e.g.,compliance information or the like).

The printed circuit board 2922 of the electronic circuit system 2900includes a substrate 2924, a first actuation portion 2926 and a secondactuation portion 2946. The substrate 2924 of the printed circuit board2922 includes the electrical components for the electronic circuitsystem 2900 to operate as desired. For example, the electricalcomponents can be resistors, capacitors, inductors, switches,microcontrollers, microprocessors and/or the like. The printed circuitboard may also be constructed of materials other than a flexiblesubstrate such as a FR4 standard board (rigid circuit board).

As shown in FIGS. 30-36, the first actuation portion 2926 includes afirst electrical conductor 2934 and defines an opening 2928 having aboundary 2929. The opening 2928 of the first actuation portion 2926 isconfigured to receive a protrusion 2726 of the electronic circuit systemactuator 2724 of the safety lock 2700. The boundary 2929 of the firstopening 2928 has a discontinuous shape, such as, for example, a teardropshape, that includes a stress concentration riser 2927. Thediscontinuity and/or the stress concentration riser 2927 of the boundary2929 can be of any suitable shape to cause the substrate 2924 to deformin a predetermined direction when the protrusion 2726 of the actuator2724 of the safety lock 2700 is moved relative to the opening 2928.

The opening 2928 is defined adjacent the first electrical conductor 2934that electronically couples the components included in the electroniccircuit system 2900. The first electrical conductor 2934 includes afirst switch 2972, which can be, for example a frangible portion of thefirst electrical conductor 2934. In use, when the safety lock 2700 ismoved from a first position (see e.g., FIG. 34) to a second position(see e.g., FIG. 35), the actuator 2724 moves in a directionsubstantially parallel to a plane defined by a surface of the firstactuation portion 2926 of the substrate 2924. The movement of theactuator 2724 causes the protrusion 2726 to move within the firstopening 2928, as indicated by the arrow EE in FIG. 35. The movement ofthe protrusion 2726 tears the first actuation portion 2926 of thesubstrate 2924, thereby separating the portion of the first electricalconductor 2934 including the first switch 2972. Said another way, whenthe safety lock 2700 is moved from its first position to its secondposition (see e.g., FIG. 44), the actuator 2724 moves irreversibly thefirst switch 2972 from a first state (e.g., a state of electricalcontinuity) to a second state (e.g., a state of electricaldiscontinuity). Said yet another way, when the safety lock 2700 is movedfrom its first position to its second position, the actuator 2724disrupts the first electrical conductor 2934.

The second actuation portion 2946 includes a second electrical conductor2935 and defines an opening 2945, having a boundary 2949 and a tearpropagation limit aperture 2948. As shown in FIGS. 34-36, the opening2945 of the second actuation portion 2946 is configured to receive aportion of an actuator 2520 of the base 2510. The boundary 2949 of theopening 2945 has a discontinuous shape that includes a stressconcentration riser 2947. The discontinuity and/or the stressconcentration riser 2947 of the boundary 2949 can be of any suitableshape to cause the substrate 2924 to deform in a predetermined directionwhen the actuator 2520 of the base 2510 is moved in a proximal directionrelative to the opening 2945, as shown by the arrow FF in FIG. 36.

The second electrical conductor 2935 includes a second switch 2973disposed between the opening 2945 and the tear propagation limitaperture 2948, which can be, for example, a frangible portion of thesecond electrical conductor 2935. In use, when the base 2510 is movedfrom its first position to its second position (see e.g., FIGS. 45 and47), the actuator 2520 moves in a proximal direction, substantiallyparallel to a plane defined by a surface of the second actuation portion2946 of the substrate 2924. The proximal movement of the actuator 2520tears the second actuation portion 2946 of the substrate 2924, therebyseparating the portion of the second electrical conductor 2935 includingthe second switch 2973. Said another way, when the base 2510 is movedfrom its first position to its second position, the actuator 2520 movesirreversibly the second switch 2973 from a first state (e.g., a state ofelectrical continuity) to a second state (e.g., a state of electricaldiscontinuity). The tear propagation limit aperture 2948 is configuredto limit the propagation of the tear in the substrate 2924 in theproximal direction. Said another way, the tear propagation limitaperture 2948 is configured to ensure that the tear in the substrate2924 does not extend beyond the tear propagation limit aperture 2948.The tear propagation limit aperture 2948 can be any shape configured tostop the propagation of a tear and/or disruption of the substrate 2924.For example, the tear propagation limit aperture 2948 can be ovalshaped. In other embodiments, the proximal boundary of the tearpropagation limit aperture 2948 can be reinforced to ensure that thetear in the substrate 2924 does not extend beyond the tear propagationlimit aperture 2948. Although specifically described above, in otherembodiments, the safety lock 2700 and base 2510 can be configured tointeract with mechanical and/or optical switches to produce anelectronic output in a reversible manner.

FIGS. 37 and 38 show the cover 2190 of the delivery device 2000. Thecover 2190 can be any suitable configuration and can include anysuitable feature. For example, the cover 2190 includes openings 2195 andnotches 2194. In some embodiments, the openings 2195 can receive inserts(not shown). The inserts can be flexible inserts and can increasefriction between the cover 2190 and a surface. For example, the insertscan increase the friction between the cover 2190 and a surface on whichthe delivery device 2000 is placed, to prevent sliding. The notches 2194are disposed at the proximal end of the cover 2190. In some embodiments,the notches 2194 can be used to reduce the material needed tomanufacture the cover 2190.

The cover 2190 includes a proximal end portion 2191 and a distal endportion 2192, and defines a cavity 2196, and status windows 2199. Thecavity 2196 of the cover 2190 is configured to receive at least aportion of the housing 2100. When the portion of the housing 2100 isdisposed within the cover 2190, the status windows 2199 aresubstantially aligned with the status windows 2130 and 2160 defined bythe housing 2100. Thus, a user can visually inspect a status of thedelivery device 2000 and/or the naloxone composition 2220 via the statuswindows of the cover 2190 and the status windows 2130 and 2160 of thehousing 2100. In other embodiments, however, such as those containing amedicament that is sensitive to ultraviolet (UV) radiation, the cover2190 need not include status windows 2199.

The proximal end portion 2191 of the cover 2190 defines apertures 2193configured to receive the cover retention protrusions 2104 of thehousing 2100 (shown in FIG. 5). In this manner, the apertures 2193 andthe cover retention protrusions 2104 of the housing 2100 removablyretain the cover 2190 about at least a portion of the housing 2100. Saidanother way, the apertures 2193 and the cover retention protrusions 2104of the housing 2100 are configured such that the cover 2190 can beremoved from a portion of the housing 2100 and then replaced about theportion of the housing 2100.

As described above, the electronic circuit system 2900 can be actuatedwhen the housing 2100 is at least partially removed from the cover 2190.More particularly, the distal end portion 2192 of the cover 2190includes the battery isolation protrusion 2197. The battery isolationprotrusion 2197 is configured to be removably disposed between thesecond surface 2966 of the battery assembly 2962 and the contact portion2918 of the distal end portion 2916 of the battery clip 2910, asdescribed above.

FIGS. 39-42 show the safety lock 2700 of the delivery device 2000. Thesafety lock 2700 of the delivery device 2000 includes a proximal surface2730, a distal surface 2740 opposite the proximal surface 2730, and aneedle sheath 2810. The safety lock 2700 defines a needle sheathaperture 2703 and a battery isolation protrusion aperture 2728. Thebattery isolation protrusion aperture 2728 is configured to receive thebattery isolation protrusion 2197 of the cover 2190 to allow the batteryisolation protrusion 2197 to be disposed within the electronic circuitsystem cavity 2137 and/or in engagement with the electronic circuitsystem 2900, as described above. Similarly stated, the battery isolationprotrusion aperture 2728 of the safety lock 2700 is aligned with thebattery isolation protrusion aperture 2135 of the housing 2100 and thus,the battery isolation protrusion 2197 can extend therethrough to bedisposed within the electronic circuit system cavity 2137 when the cover2190 is disposed about a portion of the housing 2100.

The proximal surface 2730 of the safety lock 2700 includes a safety lockprotrusion 2702, a stopper 2727, an electronic circuit system actuator2724, two opposing pull-tabs 2710, and an engagement portion 2720. Asdescribed above, when the safety lock 2700 is in a first (locked)position, the safety lock protrusion 2702 is configured to be disposedin the space 2556 defined between the extensions 2553 of the distal endportion 2552 of the release member 2550 (see e.g., FIG. 18).Accordingly, the safety lock protrusion 2702 is configured to preventthe extensions 2553 from moving closer to each other, thereby preventingproximal movement of the release member 2550 and/or delivery of themedicament 2220. The stopper 2727 of the safety lock 2700 is aprotrusion extending from the proximal surface 2730 of the safety lock2700. The stopper 2727 is configured to contact a portion of the housing2100 to limit the proximal movement of the safety lock 2700 relative tothe housing 2100 and therefore, and inadvertent delivery of a portion ofthe naloxone composition 2220. In other embodiments, the stopper 2727can be any structure configured to limit the proximal movement of thesafety lock 2700.

The electronic circuit system actuator 2724 of the safety lock 2700 hasan elongated portion 2725 and a protrusion 2726. The elongated portion2725 extends in a proximal direction from the proximal surface 2730. Inthis manner, the elongated portion 2725 can extend through a safety lockactuator opening 2524 of the base 2510 (see e.g., FIGS. 14 and 15) andwithin the safety lock actuator groove 2133 of the housing 2100 and thesafety lock actuator groove 2179 of the electronic circuit systemhousing 2170. The protrusion 2726 extends in a direction substantiallytransverse to the elongated portion 2725 and/or substantially parallelto the proximal surface 2730 of the safety lock 2700. As describedabove, the opening 2928 of the first actuation portion 2926 of theprinted circuit board 2922 is configured to receive the protrusion 2726of the actuator 2724 of the safety lock 2700.

The pull-tabs 2710 of the safety lock 2700 include a grip portion 2712and indicia 2713. The grip portion 2712 of the pull-tabs 2710 providesan area for the user to grip and/or remove the safety lock 2700 from therest of the medicament delivery system 2700. The indicia 2713 provideinstruction on how to remove the safety lock 2700. In some embodiments,the indicia 2713 can be extruded through the pull-tabs 2710 (e.g.,cut-outs defined by the pull-tabs 2710), thereby allowing a user tovisually inspect a portion of the base 2510 and/or the housing 2100while the safety lock 2700 is coupled thereto. In some embodiments, forexample, indicia 2713 can indicate the direction the user should pullthe safety lock 2700 to remove the safety lock 2700. The distal endsurface 2740 also includes indicia 2741 (see e.g., FIG. 40).

The engagement portion 2720 of the safety lock 2700 includes engagementmembers 2721. The engagement members 2721 extend in a proximal directionfrom the proximal surface 2730. The engagement members 2721 have tabs2722 that extend from a surface of the engagement members 2721. The tabs2722 are configured to engage an outer surface 2815 of the needle sheath2810.

As shown in FIG. 42, the needle sheath 2810 includes the distal endportion 2812, a proximal end portion 2811 and a rib 2816. The needlesheath 2810 also defines a bore 2813. The bore 2813 is configured toreceive the needle 2360 and/or a distal end portion of the 2372 of thecarrier 2370. In some embodiment, an inner surface of the needle sheath2810 defining bore 2813 forms a friction fit with the distal end portion2370 of the carrier 2370. The bore 2813 also receives a distal plug(e.g., a porex plug or the like) disposed at or near the distal endportion 2812 of the needle sheath 2810. In this manner, the needlesheath 2810 can protect the user from the needle 2360 and/or can keepthe needle 2360 sterile before the user actuates the delivery device2000.

The distal end portion 2812 of the needle sheath 2810 is configured tobe inserted into a space defined between the tabs 2722 of the engagementmembers 2721 of the safety lock 2700. The tabs 2722 are angled and/orbent towards the distal direction to allow the distal end portion 2812of the needle sheath 2810 to move between the engagement members 2721 ina distal direction, but not in a proximal direction. Similarly stated,the tabs 2722 include an edge that contacts the outer surface 2815 ofthe needle sheath 2810 to prevent the safety lock 2700 from moving in adistal direction relative to the needle sheath 2810. More specifically,the needle sheath 2810 is disposed between the tabs 2722 in such a waythat the rib 2816 is disposed in a distal position relative to the tabs2722. In this manner, the needle sheath 2810 is removed from the needle2360 when the safety lock 2700 is moved in a distal direction withrespect to the housing 2100 (see e.g., FIG. 44).

An operation of the delivery device 2000 (or drug product 2000) isdescribed below with reference to FIGS. 43-52. The delivery device 2000is first enabled by moving the medicament delivery device 2000 from afirst configuration to a second configuration by moving the cover 2190from a first position to a second position relative to the housing 2100,as indicated by the arrow GG in FIG. 43. When the cover 2190 is movedwith respect to the housing 2100 in the direction GG, the batteryisolation protrusion 2197 is removed from the area between the batteryclip 2910 and the second surface 2966 of the battery assembly 2962. Inthis manner, the battery assembly 2962 is operatively coupled (e.g.,electrically coupled or connected) to the electronic circuit system 2900when the cover 2190 is removed, thereby providing power to theelectronic circuit system 2900. Similarly stated, this arrangementallows the electronic circuit system 2900 to be actuated when the cover2190 is removed.

When power is provided, as described above, the electronic circuitsystem 2900 can output one or more predetermined electronic outputs. Forexample, in some embodiments, the electronic circuit system 2900 canoutput an electronic signal associated with recorded speech to theaudible output device 2956. Such an electronic signal can be, forexample, associated with a .WAV file that contains a recordedinstruction, instructing the user in the operation of the deliverydevice 2000. Such an instruction can state, for example, “Remove thesafety tab near the base of the auto-injector.” The electronic circuitsystem 2900 can simultaneously output an electronic signal to one and/orboth of the LEDs 2958A, 2958B thereby causing one and/or both of theLEDs 2958A, 2958B to flash a particular color. In this manner, theelectronic circuit system 2900 can provide both audible and visualinstructions to assist the user in the initial operation of the deliverydevice 2000.

In other embodiments, the electronic circuit system 2900 can output anelectronic output associated with a description and/or status of thedelivery device 2000 and/or the naloxone composition 2220 containedtherein. For example, in some embodiments, the electronic circuit system2900 can output an audible message indicating the symptoms for which thenaloxone composition 2220 should be administered, the expiration date ofthe naloxone composition 2220, the dosage of the naloxone composition2220, and/or the like. In some embodiments, the electronic circuitsystem 2900 can output an audible message stating, “If ready to use thedelivery device, pull off the red safety guard.” The electronic circuitsystem 2900 can also simultaneously output an electronic signal to oneand/or both of the LEDs 2958A, 2958B, thereby causing one and/or both ofthe LEDs 2958A, and 2958B to stop flashing, change color or the like.

As described above, the delivery device 2000 can be repeatedly movedbetween the first configuration and the second configuration when thecover 2190 is moved repeatedly between the first position and the secondposition respectively. Said another way, the cover 2190 can be removedand replaced about the housing 2100 any number of times. When the cover2190 is moved from the second position to the first position, thebattery isolation protrusion 2197 is inserted between the battery clip2910 and the second surface 2966 of the battery assembly 2962,deactivating the electronic circuit system 2900. When the cover is movedfrom the first position to the second position a second time, theelectronic circuit system 2900 is once again activated. In this manner,the cover 2190 can be removed and the electronic circuit system 2900 canoutput the electronic output without compromising the sterility of theneedle 2360.

After the cover 2190 is removed from the housing 2100, the deliverydevice 2000 can be moved from the second configuration (FIG. 43) to athird configuration (FIG. 44) by moving the safety lock 2700 from afirst position to a second position. The safety lock 2700 is moved froma first position to a second position by moving the safety lock 2700with respect to the housing 2100 in the direction shown by the arrow HHin FIG. 44. When the safety lock 2700 is moved from the first positionto the second position, the safety lock protrusion 2702 is removed frombetween the extensions 2553 of the release member 2550, thereby enablingthe medicament delivery mechanism 2300. Moreover, as shown in FIGS. 34and 35, when the safety lock 2700 is moved from the housing 2100, theactuator 2724 of the safety lock 2700 moves in the direction EE as shownin FIG. 35, irreversibly moving the first switch 2972 from a first state(e.g., a state of electrical continuity) to a second state (e.g., astate of electrical discontinuity). When the actuator 2724 of the safetylock 2700 irreversibly moves the first switch 2972 of the electroniccircuit system 2900 to the second state, the electronic circuit system2900 can output one or more predetermined electronic outputs. Forexample, in some embodiments, a processor (not shown) can output anelectronic signal associated with recorded speech to the audible outputdevice 2956. Such an electronic signal can be, for example, associatedwith a recorded message notifying the user of the status of the deliverydevice 2000. The electronic circuit system 2900 can also simultaneouslyoutput an electronic signal to one and/or both of the LEDs 2958A, 2958B,thereby causing one and/or both of the LEDs 2958A, and 2958B to stopflashing, change color or the like.

In some embodiments, the first actuation portion 2926 and the actuator2724 can be configured such that the actuator 2724 must move apredetermined distance before the actuator 2724 engages the boundary2929 of the opening 2928. For example, in some embodiments, the actuator2724 must move approximately 0.200 inches before the actuator 2724engages the boundary 2929 of the opening 2928. In this manner, thesafety lock 2700 can be moved slightly without irreversibly moving thefirst switch 2972 of the electronic circuit system 2900 to the secondstate. Accordingly, this arrangement will permit the user toinadvertently and/or accidentally move the safety lock 2700 apredetermined distance without actuating the electronic circuit system2900.

In some embodiments, the electronic circuit system 2900 can beconfigured to output the status message for a predetermined time period,such as, for example, five seconds. After the predetermined time periodhas elapsed, the electronic circuit system 2900 can output an audiblemessage further instructing the user in the operation of the deliverydevice 2000. Such an instruction can state, for example, “Place the baseof the auto-injector against the patient's thigh. To complete theinjection, press the base firmly against the patient's thigh.” In someembodiments, the electronic circuit system 2900 can simultaneouslyoutput an electronic signal to one and/or both of the LEDs 2958A, 2958B,thereby causing one and/or both of the LEDs 2958A, and 2958B to flash aparticular color. In this manner, the electronic circuit system 2900 canprovide both audible and/or visual instructions to assist the user inthe placement and actuation of the delivery device 2000. In someembodiments, the electronic circuit system 2900 can be configured torepeat the instructions after a predetermined time period has elapsed.

As described above, in other embodiments, the delivery device 2000and/or the electronic circuit system 2900 can have a network interfacedevice (not shown) configured to operatively connect the electroniccircuit system 2900 to a remote device (not shown) and/or acommunications network (not shown). For example, in some embodiments,the electronic circuit system 2900 can include a wireless networkinterface having the structure and function as shown and described inU.S. Pat. No. 8,226,610, entitled “Medical Injector with ComplianceTracking and Monitoring,” which is incorporated herein by reference inits entirety. In some embodiments, the electronic circuit system 2900can include a radio is configured to electronically communicate with acomputing device via a wireless protocol (e.g., Bluetooth®) as shown anddescribed in U.S. patent application Ser. No. 14/142,287, entitled“Devices, Systems and Methods for Locating and Interacting withMedicament Delivery Systems,” filed on Dec. 27, 2013, which isincorporated herein by reference in its entirety. In this manner, theelectronic circuit system 2900 can send a wireless signal notifying aremote device that the safety lock 2700 of the delivery device 2000 hasbeen removed and that the delivery device 2000 has been armed. In otherembodiments, the electronic circuit system 2900 can send a wirelesssignal (e.g., a wireless 911 call) notifying an emergency responder thatthe delivery device 2000 has been armed, for example, via removal of thesafety lock 2700.

In other embodiments, the protrusion 2726 extending from the actuator2724 of the safety lock 2700 can include a conductive element or thelike that can engage a first actuation portion structurally and/orfunctionally similar to the first actuation portion 2926. In thismanner, the movement of the conductive element relative to the firstactuation portion can actuate an electronic circuit system to output anelectronic output. For example, in some embodiments, the conductiveelement can be in electrical communication with the first actuationportion thereby causing a short, a fault, and/or completing a circuit.Thus, when the safety lock 2700 is moved relative to the housing 2100the short, fault, and/or completed circuit can be transitioned to asecond electrical state operable in outputting the electrical output.

After the safety lock 2700 is moved from the first position to thesecond position, the delivery device 2000 can be moved from the thirdconfiguration (FIG. 44) to a fourth configuration (FIGS. 45-48) bymoving the base 2510 from a first position to a second position.Similarly stated, the delivery device 2000 can be actuated by the systemactuator assembly 2500 by moving the base 2510 proximally relative tothe housing 2100. In some instances, the base 2510 is moved from itsfirst position to its second position by placing the delivery device2000 against the body of the patient and moving the base 2510 withrespect to the housing 2100 in the direction shown by the arrow II inFIG. 45.

As described above, the electronics actuator 2520 of the base 2510actuates the electronic circuit 2900 to trigger a predetermined outputor sequence of outputs when the base 2510 is moved from its firstposition to its second position. When the electronics actuator 2520 ismoved in a proximal direction relative to the opening 2945, as shown bythe arrow FF in FIG. 36, the electronic circuit system 2900 is actuatedto output one or more predetermined electronic outputs. For example, insome embodiments, the electronic circuit system 2900 can output anelectronic signal associated with recorded speech to the audible outputdevice 2956. Such an electronic signal can be, for example, associatedwith an audible countdown timer, instructing the user on the duration ofthe injection procedure. Said another way, if it takes, for example, tenseconds to complete an injection, an audible countdown timer can countfrom ten (or five) to zero ensuring that the user maintains the deliverydevice 2000 in place for the full ten (or five) seconds. In otherembodiments, the electronic signal can be, for example, associated witha recorded message notifying the user that the injection is complete,instructing the user on post-injection disposal and safety procedures,instructing the user on post-injection medical treatment or the like.Such a status message can state, for example, “The injection is nowcomplete. Please seek further medical attention from a doctor.”

The electronic circuit system 2900 can also simultaneously output anelectronic signal to one and/or both LEDs 2958A, 2958B, thereby causingone and/or both LEDs 2958A and 2958B to stop flashing, change color orthe like, to provide a visual indication that the injection is complete.In other embodiments, the electronic circuit system 2900 can send awireless signal notifying a remote device that the injection iscomplete. In this manner, a patient's compliance and/or adherence withthe use of the system can be monitored.

In some embodiments, the second actuation portion 2946 and theelectronics actuator 2520 of the base 2510 can be configured such thatthe base 2510 and/or the actuator 2520 is moved a predetermined distancebefore the electronics actuator 2520 engages the boundary 2949 of theopening 2945. For example, in some embodiments, the electronics actuator2520 must move approximately 0.200 inches before the actuator 2520engages the boundary 2949 of the opening 2945. In this manner, the base2510 can be moved a predetermined distance without irreversibly movingthe second switch 2973 of the electronic circuit system 2900 to thesecond state. Accordingly, this arrangement will permit the user toinadvertently and/or accidentally move the base 2510 without actuatingthe electronic circuit system 2900.

In a substantially concurrent process, moving the base 2510 from thefirst position to the second position places the protrusions 2515 on theproximal surface 2511 of the base 2510 into contact with the taperedsurfaces 2557 of the extensions 2553 of the release member 2550, therebymoving the extensions 2313 together. The inward movement of theextensions 2553 results in the engagement surfaces 2554 of the releasemember 2550 being disengaged from the base release surface 2126 of thehousing 2100, thereby allowing the release member 2550 to be movedproximally along its longitudinal axis as the spring 2576 expands, asshown by the arrow JJ in FIG. 47.

When the base 2510 is moved from the first position to the secondposition, the system actuator assembly 2500 actuates the medicamentdelivery mechanism 2300, thereby placing the delivery device 2000 in itsfourth configuration (i.e., the needle insertion configuration), asshown in FIGS. 45-48. More particularly, when the delivery device 2000is placed in its fourth configuration, the puncturer 2575 of the releasemember 2550 is placed in contact with and/or disposed through thefrangible seal 2413 of the gas container 2410. After the frangible seal2413 has been punctured, an actuating volume of the compressed gas flowsfrom the gas container 2410, into the portion of the gas cavity 2151proximal to the seal member 2574 of the release member 2550 and into theportion of the medicament cavity 2139 proximal to the seal member 2339of the movable member 2330 via the gas passageway 2156 of the proximalcap 2103. Thus, the gas exerts a force (e.g., associated with anincrease in pressure in the medicament cavity 2139) on the movablemember 2330 that is sufficient to move the movable member 2330, thecarrier 2370 (and the needle 2360), and the medicament container 2200 inthe distal direction within the medicament cavity 2139, as shown by thearrow KK in FIG. 48.

When the carrier 2370 moves distally within the medicament cavity 2139in response to movement of the movable member 2330, the carrier 2370 andthe medicament container 2200 are in a first configuration andcollectively move toward a second configuration. In this manner, themedicament container 2200 and the needle 2360 contemporaneously movewith the movable member 2330 and/or the carrier 2370 in a distaldirection. The movement of the needle 2360 in a distal direction resultsin a distal end portion 2362 of the needle 2360 exiting the housing 2100and entering the body of a patient via the needle aperture 2513 definedby the base 2510.

Since the retraction spring 2351 is disposed between the shoulder 2378of the carrier 2370 and the distal surface of the housing 2100 (asdescribed above), the force exerted by the expansion of the gas issufficient to overcome a force exerted by the retraction spring 2351 andas such, the retraction spring 2351 is transitioned toward a compressedconfiguration. In addition, the cap 2250 of the medicament container2200 is in contact with the ribbed portion 2376 of the carrier 2370 insuch a manner that an amount of force sufficient to move the cap 2250relative to the ribbed portion 2376 in the distal direction is greaterthan an amount of force exerted to transition the retraction spring 2351towards its compressed configuration. Thus, the movable member 2330, themedicament container 2200, and the carrier 2370 are moved concurrentlywithin the medicament cavity 2139 in response to the force exerted bythe expansion of the gas.

More specifically, in this embodiment, the inner volume of the gascontainer 2410 is about 0.0625 in³ and can contain and/or store thepressurized gas (e.g., prior to the frangible seal 2413 being punctured)at about 1100 psi. In some instances, the pressure and/or volume of thegas container 2410 can be selected in association with, for example, avolume of the naloxone composition 2220 disposed in the medicamentcontainer 2200, a length of the medicament container 2200, a position ofthe medicament container 2200 within the medicament cavity 2139, and/ora stroke length of the movable member 2330. In this manner, the drugproduct 2000 can produce certain desired performance characteristicsduring the delivery of the naloxone composition 2220. Suchcharacteristics can include, for example, a minimum time for insertionof the needle 2360, a repeatable needle insertion depth, a consistentdelivery volume, and the like.

For example, in some embodiments, the volume and/or pressure of the gaswithin the gas container 2410 can be configured to generate a desiredamount of pressure and/or force within the medicament cavity 2139 toreduce an amount of time to deliver the naloxone composition 2220 to thepatient. For example, the pressure at which the gas is stored within thegas container 2410 prior to the actuation of the delivery device 2000can be associated with a time of injection, wherein an increase in thegas pressure results in a decrease in time of injection. In someembodiments, the system actuation assembly 2500, the medicament deliverymechanism 2300 and/or the drug product 2000 is configured to deliver thedose of naloxone composition 2220 in less than about two seconds. Insome embodiments, the system actuation assembly 2500, the medicamentdelivery mechanism 2300 and/or the drug product 2000 is configured todeliver the dose of naloxone composition 2220 in less than about 0.5seconds. The increase in pressure, however, can reach a point (e.g.,about 1100 psi) at which only a nominal reduction in the time ofinjection occurs as the gas pressure increases, as shown in the graph ofFIG. 49 (which is a representative graph of a relationship betweenpressure and a time of an injection event of the delivery device 2000).In some embodiments, further reductions in the time of injection can beachieved via an increase in the size or gauge of the needle 2360.

After the carrier 2370 has been moved within the medicament cavity 2139a predetermined distance (e.g., associated with the insertion of theneedle 2360 into the patient), the carrier 2370 and the medicamentcontainer 2200 are then moved from the first configuration to the secondconfiguration. For example, in some embodiments, the retraction spring2351 can be fully compressed (e.g., a solid configuration) and canprevent the carrier 2370 from moving further in the distal direction. Inother embodiments, a portion of the carrier 2370 and/or a portion of themedicament container 2200 can contact the housing 2100 when the needleinsertion operation is completed, thereby limiting further distalmovement of the carrier 2370 and the needle 2360 coupled thereto. Withthe distal movement of the carrier 2370 prevented, the pressure withinthe gas chamber continues to exert the force on the movable member 2330and as such, the movable member 2330 continues to transmit the portionof the force on the elastomeric member 2217 disposed in the medicamentcontainer 2200.

With the naloxone composition 2220 under pressure and with at least aportion of the naloxone composition 2220 being an incompressible fluid(as described herein), the movable member 2330 and the medicamentcontainer 2200 act as a substantially solid rod. The force exerted bythe expansion of the gas on the movable member 2330 is, therefore,transferred through the movable member 2330 and the medicament container2200 and in turn, the force is exerted by the cap 2250 on the ribbedportion 2376 of the carrier 2370. The force exerted by the cap 2550 onthe ribbed portion 2376 is sufficient to overcome a friction force orthe like associated with the “snap fit” between the cap 2250 and theribbed portion 2376. Thus, when the distal movement of the carrier 2370is prevented, the force exerted by the expansion of the gas on themovable member 2330 is sufficient to move the medicament container 2200in the distal direction relative to the carrier 2370 to a distalposition, as indicated by the arrow LL in FIG. 51. In some embodiments,the movement of the medicament container 2200 relative to the carrier2370 can be substantially immediately after the carrier 2370 is placedin the distal most position within the medicament cavity 2139. Thus,substantially the same force is exerted to move the medicament container2200 relative to the carrier 2370 as was exerted at the end of thedistal movement of the carrier 2370 (e.g., at the end of the needleinsertion).

As the medicament container 2200 moves relative to the carrier 2370, theproximal end portion 2361 of the needle 2360 contacts and punctures theseal 2251 of the medicament container 2200 to establish fluidcommunication between the lumen 2363 of the needle 2360 and the innervolume of the medicament container 2200 containing the naloxonecomposition 2220. After the medicament container 2200 is placed incontact with a distal surface of the carrier 2370, the medicamentcontainer 2200 is prevented from moving in the distal direction relativeto the carrier 2370, thereby placing the delivery device 2000 in a fifthconfiguration as shown in FIG. 51.

With the distal movement of the medicament 2200 prevented, the pressurewithin the gas chamber continues to exert a force on the movable member2330 and as such, the movable member 2330 continues to transmit aportion of the force on the elastomeric member 2217 disposed in themedicament container 2200, to transition the delivery device 2000 fromthe fifth configuration to a sixth configuration (i.e., the injectionevent). With the lumen 2363 of the needle 2360 in fluid communicationwith the medicament container 2200, the force exerted by the movablemember 2330 (e.g., in response to the force exerted by the expansion ofthe gas) on the elastomeric member 2217 is sufficient to move theelastomeric member 2217 within the medicament container 2200 in thedistal direction, as indicated by the arrow MM in FIG. 52. As the pistonrod 2333 of the movable member 2330 moves within the medicamentcontainer 2200, the elastomeric member 2217 generates a pressure actingupon the naloxone composition 2220 contained within the medicamentcontainer 2200, thereby allowing at least a portion of the naloxonecomposition 2220 to flow out of the medicament container 2200, throughthe lumen 2360 defined by the needle 2360, and into the body of thepatient.

The portion of the gas cavity 2151 proximal to the seal member 2574 ofthe release member 2550, the gas passageway 2156 of the proximal cap2103, and the portion of the medicament cavity 2139 proximal to the sealmember 2339 of the movable member 2330 (collectively referred to as “gaschamber”) define a volume that is about 0.5 in³, prior to the frangibleseal 2413 being punctured and that has a pressure substantially equal toatmospheric pressure (e.g., 14.7 psi) prior to actuation of the device.Thus, when the gas container 2410 is transitioned to an actuated statesuch as, for example, when the puncturer 2575 punctures the frangibleseal 2413, the compressed gas flows from the gas container 2410 having avolume of about 0.0625 in³ and a pressure of about 1100 psi into the gaschamber having a larger volume of about 0.5 in³ and a lower pressureabout 14.7 psi. Thus, the gas expands in the gas chamber which, in turn,increases the pressure therein, and the increase in pressure exerts aforce on the movable member 2330 to move the movable member 2330 withinthe medicament cavity 2139, as described above.

The movement of the movable member 2330 in response to the increase inpressure within the gas chamber, however, increases the volume of thegas chamber. Similarly, in some instances, the increase in pressurewithin the gas chamber can exert a force on the release member 2550 thatis sufficient to move the release member 2550 in the distal directionwhich in turn, compresses the spring 2576 disposed about the releasemember 2550 to a substantially solid configuration (e.g., completelycompressed). Thus, the movement of the release member 2550 in responseto the increase in the pressure within the gas chamber also increasesthe volume of the gas chamber. As a result, pressure within the gaschamber decreases as the volume of the gas chamber increases in responseto the movement of the movable member 2330 and the release member 2550(e.g., as determined and/or approximated by the ideal gas law expressedas P₁V₁=P₂V₂, described above). Thus, the force exerted by the expansionof the gas on the movable member 2330 decreases from a first amount atthe start of an injection event to a second amount at the end of aninjection event (i.e., the sixth configuration as shown in FIG. 52).

For example, in some embodiments, the force exerted on the movablemember 2330 at the start of the injection event can be between about 30pounds-force (lb_(f)) and about 38 lb_(f) and the force exerted on themovable member 2330 at the end of the injection event (e.g., immediatelyafter the dose of the naloxone composition 2220 is delivered through theneedle 2360) can be between about 23 lb_(f) and about 31 lb_(f),respectively. More specifically, in this embodiment, the pressure withinthe gas chamber at the start of the injection event (assuming anegligible time of gas expansion and distribution) is about 160 psi,which corresponds to about 34 lb_(f) exerted on the movable member 2330,and the pressure within the gas chamber at the end of the injectionevent is about 130 psi, which corresponds to about 27 lb_(f). In someembodiments, the force exerted on the movable member 2330 can decreasein a substantially linear manner from the first amount at the start ofthe injection event to the second amount at the end of the injectionevent. In other embodiments, the decrease in the force can benon-linear, exponential, and/or logarithmic over the duration of theinjection event.

Similarly, the movable member 2330 transmits at least a portion of theforce exerted by the expansion of the gas to the elastomeric member 2217disposed within the medicament container 2200, thereby increasing apressure within the medicament container 2200 between the elastomericmember 2217 and the seal 2251. More specifically, in some embodiments,at least a portion of the naloxone composition 2220 can be, for example,an incompressible fluid. Thus, the force exerted by the movable member2330 on the elastomeric member 2217 places the naloxone composition 2220under pressure within the medicament container 2200. In someembodiments, the pressure within the medicament container 2200 can bebetween about 525 psi and about 670 psi at the start of the injectionevent, and between about 400 psi and about 545 psi at the end of theinjection event. Specifically, in this embodiment, the pressure withinthe medicament container 2200 in response to the movable member 2330exerting a force on the elastomeric member 2217 is about 600 psi at thestart of the injection event and the pressure within the medicamentcontainer 2200 is about 490 psi at the end of the injection event.

FIG. 50 shows a representative graph of the force exerted on the movablemember 2330 by the gas pressure within the gas chamber as a function ofposition of the movable member 2330 (as calculated using nominaldimensional specifications with the gas container 2410 having a volumeof about 0.0625 in³ and a pressure of about 1100 psi). As discussedabove, the force is proportional to the pressure within the medicamentcontainer 2200 (i.e., the injection pressure). As shown, the graphillustrates the decrease in the force exerted on the movable member 2330during an injection event resulting from the increased volume of the gaschamber, as described herein. This graph also includes representativedata for the average amount of force that can be exerted on a plunger ofa manually-actuated syringe by a user's thumb. In particular, asdescribed in the Experimental Study entitled, “A Biomedical Evaluationof the Epidural Neurolysis Procedure,” published in 2012 in the 15thedition of the Pain Physician Journal, the thumb force applied byorthopedic surgeons on a plunger of a manually actuated syringe wasabout 16 lb_(f) (with a range of between about 9 lb_(f) and about 22.5lb_(f)). Although this thumb force data is not actual data taken inconnection with a manually-actuated syringe containing a naloxoneformulation, it nevertheless provides an illustration of the dynamicdifferences between injection via the device 2000 and amanually-actuated syringe. In particular, the thumb force exerted on aplunger of a manually-actuated syringe is generally constant from thestart of an injection event to the end of the injection event. Moreover,the thumb force is applied independently from any force for insertingthe needle.

In contrast, as described herein, the system actuation assembly 2500,the medicament delivery mechanism 2300 and/or the drug product 2000includes a single energy storage member that produces a force that bothinserts the needle and injects the naloxone formulation. Thus, thedesired characteristics of the needle insertion for the drug product2000 can affect the characteristics of the drug delivery. In otherwords, increasing the force applied to the movable member 2330 todecrease the needle insertion time and/or to produce a more repeatableneedle insertion can result in faster initial delivery of the naloxone(due to the increased force at the beginning of injection). Conversely,decreasing the force to reduce the rate of naloxone delivery (e.g., inan effort to reduce the rate of system absorption and/or adjust a PKcharacteristics of a delivery of the naloxone composition 2220) canimpact the needle insertion performance of the drug product 2000, therepeatability with which the seal 2251 is punctured to establish fluidcommunication between the needle 2360 and the medicament container 2200,and the like. Thus, in some embodiments, the drug product 2000 isconfigured to produce certain desired performance characteristics duringthe delivery of the naloxone composition 2220. Such characteristics caninclude, for example, a minimum time for insertion of the needle 2360, arepeatable needle insertion depth, a consistent delivery volume, and thelike.

In some embodiments, the specific characteristics of, for example, thehousing 2100, the energy storage member 2410, the movable member 2330,the medicament container 2200, and/or the needle 2360 are such that thenaloxone composition 2220 is delivered from the medicament container2200 and into the body of the patient with at least one pharmacokinetic(PK) parameter of the naloxone composition is bioequivalent to thecorresponding PK parameter resulting from the delivery of acorresponding dose of a corresponding naloxone formulation via amanually-actuated syringe. Similarly stated, the delivery device 2000(or drug product) is configured such that delivery of the naloxonecomposition 2220 from the medicament container 2200 to the body producesnaloxone bioavailability that is bioequivalent to naloxonebioavailability resulting from the delivery of a corresponding naloxoneformulation from a manually actuated syringe, as described in furtherdetail herein.

For example, in some instances, the relatively high pressure at whichthe compressed gas is stored within the gas container 2410 prior tobeing actuated and/or the relatively high pressure within the gaschamber resulting from the expansion of the gas as it exits the gaschamber 2410 can be such the delivery of the naloxone composition 2220resulting from the injection event achieves bioequivalent PKcharacteristics of a delivery of the naloxone composition 2220 otherwiseresulting from a delivery of the naloxone composition 2220 via amanually actuated syringe. For example, in some embodiments, a dose ofthe naloxone composition 2220 can be delivered into a body such that the90% confidence interval of at least one of the relative mean maximumnaloxone plasma concentration after the dose is delivered into the body(C_(max)), time to reach the maximum naloxone plasma concentration(T_(max)), area under the plasma concentration-time curve from pre-dose(time 0) extrapolated to infinity (AUC_(0-∞)), or area under the plasmaconcentration-time curve from pre-dose (time 0) to the time of the lastquantifiable concentration (T_(last)) (AUC_(0-t)) of the delivered doseto a delivered dose of a corresponding naloxone composition deliveredvia a manually-actuated syringe is within 80% to 125%. In someembodiments, a dose of the naloxone composition 2220 can be deliveredinto a body such that the 90% confidence interval of at least one of therelative mean maximum naloxone plasma concentration after the dose isdelivered into the body (C_(max)), time to reach the maximum naloxoneplasma concentration (T_(max)), area under the plasma concentration-timecurve from pre-dose (time 0) extrapolated to infinity (AUC_(0-∞)), orarea under the plasma concentration-time curve from pre-dose (time 0) tothe time of the last quantifiable concentration (T_(last)) (AUC_(0-t))of the delivered dose to a delivered dose of a corresponding naloxonecomposition delivered via a manually-actuated syringe is within 100% to125%. In some embodiments, a dose of the naloxone composition 2220 canbe delivered into a body such that the 90% confidence interval of atleast one of the relative mean maximum naloxone plasma concentrationafter the dose is delivered into the body (C_(max)), time to reach themaximum naloxone plasma concentration (T_(max)), area under the plasmaconcentration-time curve from pre-dose (time 0) extrapolated to infinity(AUC_(0-∞)), or area under the plasma concentration-time curve frompre-dose (time 0) to the time of the last quantifiable concentration(T_(last)) (AUC_(0-t)) of the delivered dose to a delivered dose of acorresponding naloxone composition delivered via a manually-actuatedsyringe is within 110% to 125%. In some embodiments, a dose of thenaloxone composition 2220 can be delivered into a body such that the 90%confidence interval of at least one of the relative mean maximumnaloxone plasma concentration after the dose is delivered into the body(C_(max)), time to reach the maximum naloxone plasma concentration(T_(max)), area under the plasma concentration-time curve from pre-dose(time 0) extrapolated to infinity (AUC_(0-∞)), or area under the plasmaconcentration-time curve from pre-dose (time 0) to the time of the lastquantifiable concentration (T_(last)) (AUC_(0-t)) of the delivered doseto a delivered dose of a corresponding naloxone composition deliveredvia a manually-actuated syringe is within 115% to 125%. In other words,the delivery of the naloxone composition 2220 via the delivery device2000 is substantially bioequivalent to the delivery of the same naloxonecomposition 2220 via a manually actuated syringe.

As shown in FIGS. 53 and 54, after the movable member 2330 moves apredetermined distance within the medicament container 2200, the gasvalve actuator 2380 of the carrier 2370 engages the gas relief valve2340 (FIG. 54) of the movable member 2330 thereby allowing thepressurized gas contained within the gas chamber to escape the gaschamber. Similarly stated, the gas valve actuator 2380 of the carrier2370 engages the gas relief valve 2340 of the movable member 2330,thereby allowing the pressurized gas contained in the gas chamber and/oron the proximal side of the seal member 2339 to pass through the gasrelief valve 2340 to be disposed on a distal side of the seal member2340. Thus, the pressure within the gas chamber (i.e., on the proximalside of the seal member 2339 is reduced, thereby ending the injectionevent. In some embodiments, the pre-injection distance between theproximal end portion of the movable member 2330 and the gas valveactuator 2380 of the carrier 2370 can be adjusted to control the amountand/or the delivered volume of the naloxone composition 2220 to beinjected and/or control a point in time during the injection event atwhich the gas relief valve 2340 is transitioned to an open state. Afterthe gas pressure within the medicament cavity 2139 decreases below acertain level, the force exerted by the retraction spring 2351 on thecarrier 2370 can be sufficient to overcome any residual pressure withinthe gas chamber and thus, the carrier 2370 is moved proximally withinthe housing 2100 (i.e., to retract), as shown by the arrow NN in FIG.54. Moreover, as shown, the retraction of the carrier 2370 moves theneedle 2360 in the proximal direction such that substantially the entireneedle 2360 is disposed in a proximal position relative to the distalsurface 2523 of the base 2510. Thus, the risk of accidental needlesticks and/or the like after the delivery of the naloxone composition2220 to the body of the patient is reduced or substantially eliminated.

Referring now to FIG. 55, a flowchart is illustrated describing a methodof using a delivery device to deliver a naloxone composition to apatient according to an embodiment. For example, a method 100 includesplacing a medicament injector against a body, at 101. The medicalinjector can be, for example substantially similar to and/or the same asthe delivery device 1000 and/or 2000 described herein. Thus, the medicalinjector includes a housing, a medicament container, a needle, and anactuation assembly. The medicament container contains and/or stores adose of the naloxone composition, such as those described herein, havinga delivered volume of at least about 0.34 ml. In other embodiments, thedose of the naloxone composition can have any suitable delivered volumeand/or fill volume such as, for example, a volume between about 0.3 mland about 2.0 ml. The needle is configured to be moved between a firstneedle position and a second needle position. In some embodiments, thefirst needle position can be such that substantially the entire needleis disposed within, for example, the housing and fluidically isolatedfrom the medicament container. In some embodiments, the second needleposition can be such that a portion of the needle extends in a distaldirection from the housing and a lumen defined by the needle is placedin fluid communication with the medicament container. The actuatorassembly includes an energy storage member, such as the gas container2410 described above, and a movable member, such as the movable member2330 described above.

The medicament injector is actuated such that the energy storage memberproduces a force on the movable member to move the needle from a firstneedle position to a second needle position to deliver the dose of thenaloxone composition from the medicament container via the needle intothe body, at 102. As described above with reference to the deliverydevice 2000, the naloxone composition can be delivered in a manner suchthat the 90% confidence interval of at least one of the relative meanmaximum naloxone plasma concentration after the dose is delivered intothe body (C_(max)), time to reach the maximum naloxone plasmaconcentration (T_(max)), area under the plasma concentration-time curvefrom pre-dose (time 0) extrapolated to infinity (AUC_(0-∞)), or areaunder the plasma concentration-time curve from pre-dose (time 0) to thetime of the last quantifiable concentration (T_(last)) (AUC_(0-t)) ofthe delivered dose to a delivered dose of a corresponding naloxonecomposition delivered via a manually-actuated syringe is within 80% to125%. In some embodiments, the naloxone composition can be delivered ina manner such that the 90% confidence interval of at least one of therelative mean maximum naloxone plasma concentration after the dose isdelivered into the body (C_(max)), time to reach the maximum naloxoneplasma concentration (T_(max)), area under the plasma concentration-timecurve from pre-dose (time 0) extrapolated to infinity (AUC_(0-∞)), orarea under the plasma concentration-time curve from pre-dose (time 0) tothe time of the last quantifiable concentration (T_(last)) (AUC_(0-t))of the delivered dose to a delivered dose of a corresponding naloxonecomposition delivered via a manually-actuated syringe is within 100% to125%. In some embodiments, the naloxone composition can be delivered ina manner such that the 90% confidence interval of at least one of therelative mean maximum naloxone plasma concentration after the dose isdelivered into the body (C_(max)), time to reach the maximum naloxoneplasma concentration (T_(max)), area under the plasma concentration-timecurve from pre-dose (time 0) extrapolated to infinity (AUC_(0-∞)), orarea under the plasma concentration-time curve from pre-dose (time 0) tothe time of the last quantifiable concentration (T_(last)) (AUC_(0-t))of the delivered dose to a delivered dose of a corresponding naloxonecomposition delivered via a manually-actuated syringe is within 110% to125%. In some embodiments, the naloxone composition can be delivered ina manner such that the 90% confidence interval of at least one of therelative mean maximum naloxone plasma concentration after the dose isdelivered into the body (C_(max)), time to reach the maximum naloxoneplasma concentration (T_(max)), area under the plasma concentration-timecurve from pre-dose (time 0) extrapolated to infinity (AUC_(0-∞)), orarea under the plasma concentration-time curve from pre-dose (time 0) tothe time of the last quantifiable concentration (T_(last)) (AUC_(0-t))of the delivered dose to a delivered dose of a corresponding naloxonecomposition delivered via a manually-actuated syringe is within 115% to125%. Thus, in some embodiments, the delivery of the naloxonecomposition via the medical injector can be substantially bioequivalentto a delivery of the naloxone composition (e.g., substantially the samedose) via the manually actuated syringe.

Although the devices described above, such as the medicament deliverydevice 2000, deliver the naloxone composition via a needle (e.g., needle2360), in other embodiments, a device can deliver a naloxone compositionvia any suitable delivery member. Such delivery members can include, forexample, a delivery nozzle (e.g., for a jet injection device, nasalspray delivery device or the like). For example, FIGS. 56 and 57 areschematic illustrations of a medicament delivery device 3000 accordingto an embodiment in a first and a second configuration, respectively.The medicament delivery device 3000 (also referred to herein as“delivery device” or a “drug product”) includes a housing 3100, amedicament container 3200, a delivery member 3360, and a medicamentdelivery assembly 3300. The housing 3100 can be any suitable size,shape, or configuration and can be made of any suitable material. Forexample, in some embodiments, the housing 3100 is an assembly ofmultiple parts formed from a plastic material that are coupled togetherto form a substantially rectangular shape when assembled. As describedin more detail below, the housing 3100 includes shoulders 3111 thatengage and/or contact a portion of the medicament delivery assembly3300.

As shown in FIGS. 56-57, the medicament container 3200 is disposedwithin the housing 3100, and can be any container suitable for storingthe medicament. In some embodiments, the medicament container 3200 canbe, for example, a vial, cartridge, ampule, prefilled syringe or thelike formed from a biocompatible material such as, for example, apharmaceutical grade metal or alloy, glass, polymer, ceramic, and/or thelike. The medicament container 3200 can have, for example, a proximalend portion and a distal end portion and can define an inner volume.

The inner volume of the medicament container 3200 can include, receive,and/or otherwise contain (i.e., is filled or partially filled with) amedicament 3220 such as, for example, an opioid antagonist. Morespecifically, in some embodiments, the medicament 3220 disposed withinthe medicament container 3200 can be a naloxone composition such asthose described herein. For example, the naloxone composition caninclude an effective amount of naloxone (i.e.,4,5-epoxy-3,14-dihydroxy-17-(2-propenyl) morphinan-6-one), or apharmaceutically acceptable salt and/or ester thereof. In someembodiments, the naloxone composition can include one or morepH-adjusting agents (e.g., at least one of hydrochloric acid, citricacid, acetic acid, phosphoric acid, or combinations thereof), one ormore tonicity-adjusting agents (e.g., at least one of dextrose,glycerin, mannitol, potassium chloride, sodium chloride, or combinationsthereof), one or more stabilizing agents, and/or the like. In someembodiments, the naloxone composition can have an osmolality betweenabout 250 to about 350 mOsm and a pH between about 3 to about 5.

The medicament container 3200 includes an elastomeric member 3217 (alsoreferred to herein as a “plunger”) formulated to be compatible with themedicament housed within the medicament container 3200 (i.e., thenaloxone composition). Similarly stated, the elastomeric member 3217 isformulated to minimize any reduction in the efficacy of the medicament3220 that may result from contact (either direct or indirect) betweenthe elastomeric member 3217 and the medicament 3220. For example, insome embodiments, the elastomeric member 3217 can be formulated tominimize any leaching or out-gassing of compositions that may have anundesired effect on the medicament 3220. The elastomeric member isdisposed within the medicament container 3200, for example, to seal theproximal end portion thereof. In some embodiments, the elastomericmember 3217 can be formulated to maintain its chemical stability,flexibility, and/or sealing properties when in contact (either direct orindirect) with a medicament 3220 over a long period of time (e.g., forup to six months, one year, two years, five years, or longer). In someembodiments, the elastomeric member 3217 can be any of the elastomericmembers shown and described in U.S. Pat. No. 8,627,816 entitled“Medicament Delivery Device for Administration of Opioid AntagonistsIncluding Formulations for Naloxone,” which is incorporated herein byreference in its entirety.

The delivery member 3360 is configured to be placed in fluidcommunication with the interior of the medicament container 3200, andprovides a pathway through which the medicament (e.g., the naloxonecomposition) 3220 can be conveyed. A distal end portion 3362 of thedelivery member 3360 is disposed outside of the housing 3100, and isconfigured be disposed within, engage and/or otherwise interact with aportion of the body B. In this manner, the medicament 3220 can bedelivered from the medicament container 3200 into the body B via thedistal end portion 3362 of the delivery member 3360.

The delivery member 3360 can be any suitable structure for deliveringthe medicament 3220, in conjunction with the medicament deliveryassembly 3300, in a manner that provides a desired set of deliveryand/or pharmacokinetic (PK) characteristics. In some embodiments, forexample, the delivery member 3360 can be a nozzle and/or atomizerthrough which the medicament 3220 can be delivered intranasally orintraorally. In other embodiments, the delivery member 3360 can be anozzle through which the medicament 3220 can be delivered via a jetinjection process. In yet other embodiments, the delivery member 3360can be a needle of the types shown and described herein.

The delivery member 3360 can be any suitable shape, size, orconfiguration. For example, in some embodiments, the delivery member3360 is a needle having any diameter and/or length to facilitate thedelivery of the medicament 3220 (i.e., the naloxone composition). Inother embodiments, the delivery member 3360 can be a nozzle and/oratomizer having a diverging flow area configured to produce a sprayhaving a desired droplet size. In yet other embodiments, the deliverymember 3360 can be a mouthpiece having an engagement portion configuredto facilitate delivery of the medicament 3220 via inhalation. Althoughthe delivery member 3360 is show in FIGS. 56 and 57 as being in a fixedposition within the housing 3100, in other embodiments, the deliverymember 3360 can be movable within the housing 3100, as described herein.

The medicament delivery assembly 3300 can be any suitable assembly,mechanism, and/or device that can transfer a force to the elastomericmember 3217 to deliver a dose of the medicament 3220 (e.g., naloxone),as described herein. As shown in FIGS. 56 and 57, the medicamentdelivery assembly 3300 includes a movable member 3330 having adeformable portion 3376 (although two distinct deformable portions areshown, in other embodiments, the movable member 3330 can include onlyone, contiguous deformable portion). The movable member 3330 is movablydisposed within the housing 3100 such that, a distal portion of themovable member 3330 is in contact with the elastomeric member 3217. Inthis manner, a force F′ can be exerted by the movable member 3330 tomove the elastomeric member 3217, thereby delivering the medicament3220.

The force F′ can be produced in any suitable fashion. In someembodiments, the force F′ can be produced by an energy storage member(not shown in FIGS. 56 and 57) of the types shown and described herein.Similarly stated, in some embodiments, the medicament delivery device3000 can automatically produce the force F′ that produces delivery ofthe medicament 3220. An “automatically produced” force is a force thatis not directly produced by a human. Examples of automatic deliverydevices include an apparatus having a compressed gas source to providethe delivery force, an apparatus having a spring to provide the deliveryforce, and an apparatus having an electric motor to provide the deliveryforce. An apparatus for automatically delivering a medicament, however,can include a manual actuator (e.g., an on/off switch, a push button, orthe like) to initiate the “automatic” delivery. In other embodiments,the force F′ can be produced manually, such as by a user directlydepressing the movable member 3330 with sufficient force to deliver themedicament 3220.

In the event of a medical emergency associated with, for example, apatient experiencing an opioid overdose, a user (e.g., a patient, afriend or family member, an untrained bystander, a medical professional,etc.) can manipulate the delivery device 3000 to administer themedicament 3220 (e.g., an opioid antagonist such as any of the naloxoneformulations described herein) to the patient. As shown in FIG. 57, theuser can manipulate the delivery device 3000 to actuate the medicamentdelivery assembly 3300, for example, by placing at least a portion ofthe delivery device 3000 in contact with or adjacent a surface of thebody B of the patient, and transitioning the delivery device 3000 to thesecond configuration. The delivery device 3000 can be actuated (ortransitioned to its second configuration) by any suitable mechanism,such as, for example, by manually application of the force F′ againstthe movable member 3330, by depressing a button disposed at a proximalend of the device, or the like.

Before actuation of the delivery device 3300 and before the force F′reaches a threshold value, the deformable portion 3376 is in contactwith the shoulders 3111 of the housing to limit and/or prevent movementof the movable member 3330 within the medicament container 3200. Asshown by the arrows AA′ in FIG. 57, when the force F′ exceeds athreshold value, at least a portion of the force F′ exerted on themovable member 3330 can deform the deformable portion 3376 of themovable member 3330. Similarly stated, when the force F′ exceeds athreshold value, the deformable portion 3376 can deform against theshoulders 3111 to move from a first configuration to a secondconfiguration. With the deformable portion 3376 in the secondconfiguration, the force F′ can move the movable member 3330 relative tothe medicament container 3200, as shown in FIG. 57. The movement of themovable member 3330 increases a pressure within a portion of themedicament container 3200 (for example, between the elastomeric member3217 and a surface of the medicament container 3200 through which thedelivery member 3360 extends) to expel the medicament 3220 from themedicament container 3200, as indicated in FIG. 57. Although describedas including the elastomeric member 3217 that is distinct from themovable member 3330, in some embodiments, the movable member 3330 can bethe elastomeric member 3217. In such embodiments, the force F′ can actdirectly or indirectly on the elastomeric member 3217 to perform thefunctions described herein.

The arrangement of the delivery mechanism 3300, the movable member 3330(including the deformable portion 3376), the delivery member 3360, andthe composition of the medicament 3220 and/or any other suitable portionof the delivery device 3000 (or drug product) can be such that themedicament 3220, when delivered, provides a desired set of deliveryand/or pharmacokinetic (PK) characteristics. In some embodiments, thespecific characteristics of the delivery device 3000 (or drug product)are such that a dose of the medicament 3220 (i.e., the naloxoneformulation) is delivered from the medicament container 3200 and intothe body of the patient (as indicated by the spray in FIG. 57) such thatat least one pharmacokinetic parameter of the naloxone composition isbioequivalent to the corresponding pharmacokinetic parameter resultingfrom the delivery of a corresponding dose of a corresponding naloxoneformulation via a manually-actuated syringe. Similarly stated, thedelivery device 3000 (or drug product) is configured such that deliveryof the medicament 3220 (i.e., the naloxone formulation) from themedicament container 3200 to the body provides naloxone bioavailabilitythat is bioequivalent to naloxone bioavailability resulting from thedelivery of a corresponding naloxone formulation from a manuallyactuated syringe. In some embodiments, the medicament delivery assembly3300 is configured to deliver the dose of the medicament 3220 (i.e., thenaloxone formulation) into the body such that the 90% confidenceinterval of at least one of the relative mean maximum naloxone plasmaconcentration after the dose is delivered into the body (C_(max)), timeto reach the maximum naloxone plasma concentration (T_(max)), area underthe plasma concentration-time curve from pre-dose (time 0) extrapolatedto infinity (AUC_(0-∞)), or area under the plasma concentration-timecurve from pre-dose (time 0) to the time of the last quantifiableconcentration (T_(last)) (AUC_(0-t)) of the delivered dose to adelivered dose of a corresponding naloxone composition delivered via amanually-actuated syringe is within 80% to 325%.

In yet other embodiments, the specific characteristics of the deliverydevice 3000 (or drug product) are such that a dose of the medicament3220 (i.e., the naloxone formulation) is delivered from the medicamentcontainer 3200 and into the body of the patient such that the 90%confidence interval of at least one of the relative mean maximumnaloxone plasma concentration after the dose is delivered into the body(C_(max)), time to reach the maximum naloxone plasma concentration(T_(max)), area under the plasma concentration-time curve from pre-dose(time 0) extrapolated to infinity (AUC_(0-∞)), or area under the plasmaconcentration-time curve from pre-dose (time 0) to the time of the lastquantifiable concentration (T_(last)) (AUC_(0-t)) of the delivered doseto a delivered dose of a corresponding naloxone composition deliveredvia a manually-actuated syringe is within 80% to 325%.

For example, in some embodiments, the medicament delivery assembly 3300is configured to deliver a dose of the naloxone composition (i.e., anyof the naloxone compositions described herein) having a delivered volumeof at least about 0.34 ml at a faster delivery rate and/or at a higherdelivery pressure than would result from the delivery of a correspondingdose via a manually-actuated syringe.

In such embodiments, the arrangement of the housing 3100 (e.g., theshoulders 3111) and the deformable portion 3376 can be such that theforce F′ exerted on the movable member 3330 decreases from a firstamount at the start of a delivery event to a second amount at the end ofthe delivery event. In some embodiments, the force exerted on themovable member 3330 can decrease as a function of how the deformableportions 3376 are moved in response to the force F′. The decrease in theforce can be, for example, linear, non-linear, exponential, and/orlogarithmic over the duration of the delivery event. In contrast, asdescribed above, a force exerted on a plunger of a manually-actuatedsyringe that is devoid of any deformable portions (such as thedeformable portion 3376) can be substantially constant throughout thestroke of the syringe. As described herein, even when delivered with adifferent delivery and/or force profile, the delivery device 3000 (ordrug product) delivers the dose of the naloxone composition such that atleast one pharmacokinetic parameter of the naloxone composition isbioequivalent to the corresponding pharmacokinetic parameter resultingfrom the delivery of a corresponding dose of a corresponding naloxoneformulation via a manually-actuated syringe.

Although the movable member 3330 is shown and described above asincluding the deformable portion 3376, in other embodiments, anysuitable portion of the medicament delivery assembly 3300 can include adeformable portion 3376 that limits movement of the movable member 3300and/or the elastomeric member 3217 until a force above a threshold valueis applied. For example, in some embodiments, the medicament deliveryassembly 3300 can include a carrier having a protrusion, surface or thelike that is configured to deform to allow movement of the movablemember (similar to the ribbed portion 2376 of the carrier 2370 describedabove with reference to the device 2000).

In some embodiments, the delivery member 3360 can be a needle, and themovable member 3330 is configured to move the needle from a first needleposition to a second needle position before the deformation of thedeformable portion 3376. In such embodiments, a distal end portion ofthe needle can be disposed outside of the housing when the needle is inthe second needle position.

Although the force F′ is described as being produced manually, in someembodiments, the medicament delivery device includes an energy storagemember configured to produce the force on the movable member.

In some embodiments, the medicament delivery assembly 3300 is configuredto deliver the dose in less than about two seconds. In some embodiments,the medicament delivery assembly 3300 is configured to deliver the dosein less than about 0.5 seconds.

Referring now to FIG. 58, a flowchart is illustrated describing a methodof using a delivery device to deliver a naloxone composition to apatient according to an embodiment. For example, a method 110 includesplacing a medicament delivery device against a body, at 111. Themedicament delivery device can be, for example substantially similar toand/or the same as the delivery device 2000 and/or 3000 describedherein. Thus, the medicament delivery device includes a housing, amedicament container, a delivery member, and a medicament deliveryassembly. The medicament container contains and/or stores a dose of thenaloxone composition, such as those described herein, having a deliveredvolume of at least about 0.34 ml. In other embodiments, the dose of thenaloxone composition can have any suitable delivered volume and/or fillvolume such as, for example, a volume between about 0.3 ml and about 2.0ml. The delivery member extends in a distal direction from the housing,and is configured to be placed in fluid communication with themedicament container. The medicament delivery assembly includes amovable member, such as the movable member 3330 described above, and adeformable portion. The deformable portion can a portion of the movablemember 3330 or any other suitable portion of the medicament deliveryassembly.

A force is applied to the movable member of the medicament deliveryassembly to deform the deformable portion of the medicament deliveryassembly and move an elastomeric member within the medicament containerto deliver the naloxone composition via the delivery member, at 112. Asdescribed above with reference to the delivery device 3000, the naloxonecomposition can be delivered in a manner such that the 90% confidenceinterval of at least one of the relative mean maximum naloxone plasmaconcentration after the dose is delivered into the body (C_(max)), timeto reach the maximum naloxone plasma concentration (T_(max)), area underthe plasma concentration-time curve from pre-dose (time 0) extrapolatedto infinity (AUC_(0-∞)), or area under the plasma concentration-timecurve from pre-dose (time 0) to the time of the last quantifiableconcentration (T_(last)) (AUC_(0-t)) of the delivered dose to adelivered dose of a corresponding naloxone composition delivered via amanually-actuated syringe is within 80% to 125%. In some embodiments,the naloxone composition can be delivered in a manner such that the 90%confidence interval of at least one of the relative mean maximumnaloxone plasma concentration after the dose is delivered into the body(C_(max)), time to reach the maximum naloxone plasma concentration(T_(max)), area under the plasma concentration-time curve from pre-dose(time 0) extrapolated to infinity (AUC_(0-∞)), or area under the plasmaconcentration-time curve from pre-dose (time 0) to the time of the lastquantifiable concentration (T_(last)) (AUC_(0-t)) of the delivered doseto a delivered dose of a corresponding naloxone composition deliveredvia a manually-actuated syringe is within 100% to 125%. In someembodiments, the naloxone composition can be delivered in a manner suchthat the 90% confidence interval of at least one of the relative meanmaximum naloxone plasma concentration after the dose is delivered intothe body (C_(max)), time to reach the maximum naloxone plasmaconcentration (T_(max)), area under the plasma concentration-time curvefrom pre-dose (time 0) extrapolated to infinity (AUC_(0-∞)), or areaunder the plasma concentration-time curve from pre-dose (time 0) to thetime of the last quantifiable concentration (T_(last)) (AUC_(0-t)) ofthe delivered dose to a delivered dose of a corresponding naloxonecomposition delivered via a manually-actuated syringe is within 110% to125%. In some embodiments, the naloxone composition can be delivered ina manner such that the 90% confidence interval of at least one of therelative mean maximum naloxone plasma concentration after the dose isdelivered into the body (C_(max)), time to reach the maximum naloxoneplasma concentration (T_(max)), area under the plasma concentration-timecurve from pre-dose (time 0) extrapolated to infinity (AUC_(0-∞)), orarea under the plasma concentration-time curve from pre-dose (time 0) tothe time of the last quantifiable concentration (T_(last)) (AUC_(0-t))of the delivered dose to a delivered dose of a corresponding naloxonecomposition delivered via a manually-actuated syringe is within 115% to125%. Thus, in some embodiments, the delivery of the naloxonecomposition via the medicament delivery device can be substantiallybioequivalent to a delivery of the naloxone composition (e.g.,substantially the same dose) via the manually actuated syringe.

In some embodiments, the force can be manually applied to movablemember. In other embodiments, the medicament delivery device includes anenergy storage member configured to produce the force. In suchembodiments, the force can be applied by actuating the energy storagemember.

The embodiments described herein can be used with any suitable opioidantagonist such as, for example, naloxone compositions or apharmaceutically acceptable salt thereof suitable for use in themedicament delivery devices disclosed herein. Such naloxone compositionscan include any of the compositions described in U.S. Pat. No. 8,627,816entitled “Medicament Delivery Device for Administration of OpioidAntagonists Including Formulations for Naloxone,” which is incorporatedherein by reference in its entirety. Accordingly, the present naloxonecompositions may be adapted for various administration routes, dependingon the apparatus in which such composition(s) are to be employed. Forexample, in some embodiments, the present compositions may be adaptedfor transmucosal administration as, e.g., a nasal spray, oralternatively as a sublingual or buccal spray. In other embodiments, thepresent naloxone compositions may be adapted for parenteraladministration as, e.g., an injectable solution.

The present compositions generally comprise an effective amount ofnaloxone, i.e., 4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one, or a pharmaceutically acceptable salt and/or esterthereof. As used herein, an “effective amount” is an amount sufficientto provide a desired therapeutic effect. For example, as describedherein, the present naloxone compositions may be useful in treatingrespiratory depression and/or other indications associated with opioidtoxicity. Accordingly, an effective amount of naloxone in the presentcompositions may be an amount sufficient to treat such respiratorydepression and/or other indications associated with opioid toxicity. Thepresent naloxone compositions typically have a concentration of4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one (or a saltand/or ester thereof) between about 0.01 mg/mL and about 10 mg/mL (e.g.,between about 0.05 mg/mL and about 2 mg/mL, or any other value or rangeof values therein, including about 0.1 mg/mL, about 0.2 mg/mL, about 0.3mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1.0 mg/mL, about 1.1mg/mL, about 1.2 mg/mL, about 1.3 mg/mL, about 1.4 mg/mL, about 1.5mg/mL, about 1.6 mg/mL, about 1.7 mg/mL, about 1.8 mg/mL, or about 1.9mg/mL).

In some embodiments, the present naloxone compositions comprise apH-adjusting agent. In some embodiments, the pH-adjusting agent includesat least one of hydrochloric acid, citric acid, acetic acid, phosphoricacid, or combinations thereof. The pH-adjusting agent may comprise anorganic and/or inorganic acid or salt thereof (e.g., alkali metal salts[Li, Na, K, etc.], alkaline earth metal [e.g., Ca, Mg, etc.] salts,ammonium salts, etc.). In other embodiments, the pH-adjusting agentincludes mixtures of one or more acids and one or more salts thereof,e.g., citric acid and citrate salts, acetic acid and acetate salts,phosphoric acid and phosphate salts, etc. In certain embodiments, thepH-adjusting agent is added in an amount sufficient to provide a pH ofthe present naloxone compositions of from about 3 to about 5 (forexample a pH of about 3.0, about 3.1, about 3.2, about 3.3, about 3.4,about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7,about 4.8, about 4.9, or about 5.0). Accordingly, the presentcompositions may comprise naloxone salts of the pH-adjusting agentemployed. For example, in one embodiment, the pH-adjusting agent isdilute aqueous hydrochloric acid, and the naloxone salt is naloxone HCl(e.g., 4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)-morphinan-6-onehydrochloride).

Solvents suitable for use in the present compositions are notparticularly limited, provided they are pharmaceutically acceptable.Accordingly, any pharmaceutically acceptable solvent in which thecomponents of the present compositions are soluble, and which does notadversely affect the stability of the present compositions and/or thenaloxone and/or naloxone salts contained therein may be employed. Forexample, in a typical composition, the solvent is sterile water (e.g.,USP grade water for injection [WFI]).

In some embodiments, the present compositions may also comprise one ormore tonicity-adjusting agents. For example, the tonicity-adjustingagent may include at least one of dextrose, glycerin, mannitol,potassium chloride, sodium chloride, or combinations thereof. Thetonicity-adjusting agent(s) may be present in an amount of from about0.1 mg/mL to about 50 mg/mL (e.g., including about 0.5 mg/mL, about 1.0mg/mL, about 2.0 mg/mL, about 3.0 mg/mL, about 4.0 mg/mL, about 5.0mg/mL, about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, about 25 mg/mL,about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, or about 45 mg/mL). Inone embodiment, the tonicity-adjusting agent is sodium chloride, and theconcentration thereof is between about 0.1 mg/mL and about 20 mg/mL.Generally, in naloxone compositions as described herein which areadapted for injection and/or intranasal delivery, tonicity-adjustingagents are added to provide a desired osmolality. In some embodiments,the osmolality of the naloxone compositions described herein is fromabout 250 to about 350 mOsm.

Because the naloxone compositions disclosed herein may be stored in themedicament container of the devices described herein for extendedperiods of time under varying storage conditions, in some embodimentsthe present compositions may further comprise stabilizers to prevent orinhibit decomposition of the naloxone during storage. Various types ofpharmaceutically acceptable stabilizers can be used, includingantioxidants (e.g. substituted phenols such as BHT, TBHQ, BHA, or propylgallate; ascorbates such as ascorboyl palmitate, sodium ascorbate,ascorbic acid), complexing agents (e.g., cyclodextrins); or chelatingagents such as EDTA (and its salts), D-gluconic acid δ-lactone, sodiumor potassium gluconate, sodium triphosphate, and sodiumhexametaphosphate.

Exemplary naloxone compositions suitable for use in the presentinvention are set forth in Table 1, below:

TABLE 1 Exemplary Naloxone Formulations. NaCl API API Mix NaCl MixVolume of Final Initial Order of Added Time Added Time Initial AdjustedFinal pH Adjuster Weight Lot WFI (g) Addition (mg) (seconds) (g)(seconds) pH pH pH (mL) (g) 1 400.01 A 554.73 110 4.5000 98 5.52 3.012.99 4.1 500.00 2 400.15 B 555.10 86 4.5269 69 5.41 6.51 6.51 0.5 502.143 400.13 A 554.95 104 4.5033 58 5.39 4.47 4.47 0.2 502.17 4 400.00 B554.58 82 4.4999 87 5.37 3.01 3.01 4.0 502.15 5 399.99 A 554.59 854.5513 74 5.40 6.49 6.49 0.2 502.16 6 400.02 B 554.81 68 4.5020 70 5.454.50 4.49 0.2 502.19 Final Formulation Solution Density = 1.0043 g/mL(Determined during the formulation process for Lot 1) Order of Addition:A = Water, Nacl, naloxone hydrochloride, pH adjuster B = Water, naloxonehydrochloride, NaCl, pH adjuster

In some embodiments, a medicament delivery device such as thosedescribed herein can be configured to automatically deliver any of thenaloxone compositions described herein. Similarly stated, in someembodiments, a medicament delivery device, after being actuated by theuser, can automatically produce (i.e., produce without any further humanintervention) a force or a range of forces to deliver the naloxonecomposition. In this manner, the force with which the naloxonecomposition is delivered is within a desired range, and is repeatablebetween different devices, users or the like. Moreover, the force and/orrange of forces can deliver the naloxone composition into a portion ofthe body in such a manner that at least one PK parameter of the naloxonecomposition is bioequivalent to the corresponding PK parameter resultingfrom the delivery of a corresponding dose of a corresponding naloxoneformulation via a manually-actuated syringe. Similarly stated, thedelivery device (or drug product) is configured such that delivery ofthe naloxone composition into the body produces naloxone bioavailabilitythat is bioequivalent to naloxone bioavailability resulting from thedelivery of a corresponding naloxone formulation from a manuallyactuated syringe or the like.

While various embodiments have been described above, it should beunderstood that they have been presented by way of example only, and notlimitation. Where schematics and/or embodiments described above indicatecertain components arranged in certain orientations or positions, thearrangement of components may be modified. While the embodiments havebeen particularly shown and described, it will be understood thatvarious changes in form and details may be made. Although variousembodiments have been described as having particular features and/orcombinations of components, other embodiments are possible having acombination of any features and/or components from any of embodiments asdiscussed above.

For example, the needles 1360 and 2360 described herein can have anydiameter and/or length to facilitate the injection of the naloxonecomposition 1220 and 2220, respectively. For example, the needles 1360and 2360 can have a length suitable to penetrate clothing and deliverthe naloxone via a subcutaneous injection and/or an intramuscularinjection. In some embodiments, the needles 1360 and 2360 can have alength of greater than 1 inch, greater than 1.5 inches, greater than 2inches, greater than 2.5 inches or greater than 3 inches. In someembodiments, the needles 1360 and 2360 can have a lumen diameter ofapproximately between 19-gauge and 31-gauge.

In some embodiments, the outer surface 2815 of the needle sheath 2810can include a cap or cover that has different material properties thanthe remainder of the needle sheath 2810. For example, in someembodiments, the outer surface 2815 can be constructed of a materialhaving greater hardness and/or rigidity than the remainder of the needlesheath 2810. This arrangement allows for sufficient structural rigidityto assemble the needle sheath 2810 within the engagement portion 2720 ofthe safety lock 2700. In other embodiments, however, the needle sheath2810 need not include an outer cover or cap. The use of a cap-lessdesign can reduce manufacturing and/or assembly costs.

Although the devices 1000, 2000 and 3000 are specifically describedabove as being configured to deliver, for example, a naloxonecomposition, in other embodiments, the devices 1000. 2000 and/or 3000can be configured to deliver any suitable medicament or therapeuticagent. In some embodiments, the medicament can be a vaccine, such as,for example, an influenza A vaccine, an influenza B vaccine, aninfluenza A (H1N1) vaccine, a hepatitis A vaccine, a hepatitis Bvaccine, a haemophilus influenza Type B (HiB) vaccine, a measlesvaccine, a mumps vaccine, a rubella vaccine, a polio vaccine, a humanpapilloma virus (HPV) vaccine, a tetanus vaccine, a diphtheria vaccine,a pertussis vaccine, a bubonic plague vaccine, a yellow fever vaccine, acholera vaccine, a malaria vaccine, a smallpox vaccine, a pneumococcalvaccine, a rotavirus vaccine, a varicella vaccine, a rabies vaccineand/or a meningococcus vaccine. In yet other embodiments, the medicamentcan include peptide hormones such as insulin and glucagon, human growthhormone (HGH), erythropoiesis-stimulating agents (ESA) such asdarbepoetin alfa, monoclonal antibodies such as denosumab andadalimumab, interferons, etanercept, pegfilgrastim, and other chronictherapies, or the like. In still other embodiments, the medicament canbe a placebo substance (i.e., a substance with no active ingredients),such as water.

Although the delivery device 2000 is shown above as including a gascontainer 2410 that is actuated by a puncturer that moves within thehousing 2100 with the release member 2550, in other embodiments a systemactuation assembly 2500 can include a puncturer that is substantiallyfixed within the housing and a gas container that moves within thehousing into contact with the puncturer upon actuation of the device.

Although the delivery devices 1000 and 2000 are shown and describedabove as being auto-injectors configured to deliver the naloxonecompositions described herein via injection through a needle (e.g., theneedle 1360 and the needle 2360, respectively), in other embodiments, amedicament delivery device can be configured to deliver the naloxonecompositions described herein via any suitable delivery member, and inany suitable manner. For example, in some embodiments, a medicamentdelivery device can include a delivery member that delivers the naloxonecomposition into the body via inhalation and/or intranasal delivery, asshown, for example in delivery device 3000. For example, in someembodiments, an energy storage member is disposed within a housing of adelivery device (drug product), and is configured to produce a force todeliver the naloxone composition from the medicament container via adelivery member such that the delivery member atomizes the naloxonecomposition. In other embodiments, a device can include deformableportions such that the application of a manually-produced force candeliver the naloxone composition from the medicament container via adelivery member such that the delivery member atomizes the naloxonecomposition.

Although the delivery device 2000 includes the electronic circuit systemcavity 2137, the gas cavity 2151, and/or the medicament cavity 2139 thatare shown and described as being fluidically and/or physically isolatedfrom each other, in other embodiments, any of the electronic circuitsystem cavity 2137, the gas cavity 2151, and/or the medicament cavity2139 can be fluidically coupled to and/or share a common boundary witheach other. In some embodiments, for example, a housing can define asingle cavity within which a medicament container, an energy storagemember and an electronic circuit system are disposed.

Although the delivery device 2000 includes the electronic circuit system2900, in other embodiments, a delivery device and/or drug product neednot include an electronic circuit system.

Although the electronic circuit system 2900 is shown and described aboveas producing an electronic output in response to the actuation of twoirreversible switches (e.g., switch 2972 and switch 2973), in otherembodiments, an electronic circuit system can produce an electronicoutput in response to an actuation of any number of reversible orirreversible switches and/or any other suitable input, command, orprompt. Suitable input for prompting an output can include, for example,an audible input by the user (e.g., the user's response to a voiceprompt produced by the electronic circuit system), an input from a“start button” depressed by the user, an input from a sensor (e.g., aproximity sensor, a temperature sensor or the like), movement of (e.g.,shaking) of the medicament delivery device, or the like. In someembodiments, an electronic circuit system can include a microphoneand/or a voice recognition module to detect a user's vocal input.

Although medical devices having two LEDs and an audio output device havebeen shown, in other embodiments the medical device might have anynumber of LEDs and/or audio output devices. Additionally, other types ofoutput devices, such as haptic output devices, can be used. In someembodiments, outputs from an electronic circuit system can include, forexample, an audible or visual output related to the composition of themedicament (e.g., an indication of the expiration date, the symptomsrequiring treatment with the medicament or the like), the use of themedicament delivery device, and/or post-administration procedures (e.g.,a prompt to call 911, instructions for the disposal of the device or thelike).

Although the electronic circuit system 2900 is shown and describedherein as being coupled the housing 2100 of the medicament deliverydevice 2000, in other embodiments, all or a portion of an electroniccircuit system can be coupled to a removable cover (e.g., cover 2190).For example, in some embodiments, such a cover can include an electroniccircuit system (the “master ECS”) including an audible output device,and the electronic circuit system can be configured to receive one ormore signals from an electronic circuit system (the “slave ECS”) coupledto the medicament delivery device. In this manner, the master ECS canreceive indications of when the safety tab has been removed, when thedevice has been actuated or the like, and can produce an audible outputas described herein. In some such embodiments, the master ECS and theslave ECS can be similar to the electronic circuit systems shown anddescribed in U.S. Pat. No. 8,172,082, entitled “Devices, Systems andMethods for Medicament Delivery,” filed on Feb. 5, 2007, which isincorporated herein by reference in its entirety.

Although the electronic circuit system 2900 is shown and described aboveas producing an electronic output in response to the removal of thesafety lock 2700 and/or movement of the base 2510, in other embodiments,any suitable component within a medicament delivery device can functionto actuate the electronic circuit system. For example, in someembodiments, a carrier (similar to the carrier 2370) can include aprotrusion configured to engage a portion of an electronic circuitsystem such that the electronic circuit system produces an output inresponse to movement of the carrier. In other embodiments, an electroniccircuit system can produce an electronic output in response to thedeformation of a portion of a movable member (e.g., the engagementportion 2379 of the carrier 2370). In such embodiments, the deformableportion may be configured to engage a portion of the electronic circuitsystem or may be configured such that a portion of the electroniccircuit system is disposed therein (e.g., a copper trace) to activatethe electronic circuit system.

In some embodiments, the electronic circuit system 2900 can be used ineither an actual medicament delivery device or a simulated medicamentdelivery device. A simulated medicament delivery device can, forexample, correspond to an actual medicament delivery device and can beused, for example, to train a user in the operation of the correspondingactual medicament delivery device.

The simulated medicament delivery device can simulate the actualmedicament delivery device in any number of ways, as shown and describedin U.S. Patent Publication No. 2008/0059133, entitled “Medical InjectorSimulation Device,” which is incorporated herein by reference in itsentirety. For example, in some embodiments, the simulated medicamentdelivery device can have a shape corresponding to a shape of the actualmedicament delivery device, a size corresponding to a size of the actualmedicament delivery device and/or a weight corresponding to a weight ofthe actual medicament delivery device. Moreover, in some embodiments,the simulated medicament delivery device can include components thatcorrespond to the components of the actual medicament delivery device.In this manner, the simulated medicament delivery device can simulatethe look, feel and sounds of the actual medicament delivery device. Forexample, in some embodiments, the simulated medicament delivery devicecan include external components (e.g., a housing, a needle guard, asterile cover, a safety lock or the like) that correspond to externalcomponents of the actual medicament delivery device. In someembodiments, the simulated medicament delivery device can includeinternal components (e.g., an actuation mechanism, a compressed gassource, a medicament container or the like) that correspond to internalcomponents of the actual medicament delivery device.

In some embodiments, however, the simulated medicament delivery devicecan be devoid of a medicament and/or those components that cause themedicament to be delivered (e.g., a needle, a nozzle or the like). Inthis manner, the simulated medicament delivery device can be used totrain a user in the use of the actual medicament delivery device withoutexposing the user to a needle and/or a medicament. Moreover, thesimulated medicament delivery device can have features to identify it asa training device to prevent a user from mistakenly believing that thesimulated medicament delivery device can be used to deliver amedicament. For example, in some embodiments, the simulated medicamentdelivery device can be of a different color than a corresponding actualmedicament delivery device. Similarly, in some embodiments, thesimulated medicament delivery device can include a label clearlyidentifying it as a training device.

The actuation of the medicament delivery device configuration switch2974 can configure the electronic circuit system 2900 to output adifferent electronic output when the medicament delivery device 2000 isa simulated delivery device than when the medicament delivery device2000 is an actual delivery device. Said yet another way, the electroniccircuit system 2900 can be configured to output a first series ofelectronic outputs when the electronic circuit system configurationswitch 2974 is in the first state and a second series of electronicoutputs when the electronic circuit system configuration switch 2974 isin the second state. In this manner, the electronic circuit systemconfiguration switch 2974 can enable the same electronic circuit system2900 to be used in both simulated medicament delivery devices and actualmedicament delivery devices. When used on an actual medicament deliverydevice, for example, the housing can be devoid of the actuationprotrusion 2165. The dual functionality of the electronic circuit system2900 can decrease the cost of production of the electronic circuitsystem 2900 of the medicament delivery device 2000.

In other embodiments, moving the electronic circuit system configurationswitch 2974 to the second state can place the electronic circuit system2900 in any number of different functional configurations. For example,moving the electronic circuit system configuration switch 2974 from thefirst state to the second state can indicate the type of medicament inthe medicament container, the dosage of the medicament and/or thelanguage of the audible electronic outputs output by the electroniccircuit system 2900.

In still other embodiments, any number of electronic circuit systemconfiguration switches can be used. For example, multiple switches canbe used to configure the electronic circuit system 2900 to output usageinstructions in any number of languages. For example, if an electroniccircuit system contained three configuration switches (e.g., switches A,B and C), switch A can correspond to English instructions, switch B toSpanish instructions and switch C to German instructions. Further,moving both switch A and B to the second state might correspond toFrench instructions. In this manner, a single electronic circuit system2900 can be configured to output instructions in multiple languages.

Although the drug product 2000 is shown and described as include a gascontainer to produce the force for insertion and injection, in otherembodiments, a drug product can include any suitable energy storagemember, such as, for example, a spring.

Pharmacokinetic Analysis

A randomized, single-blind, single-dose, two-sequence, two-periodcrossover bioavailability, safety and tolerability study in fasted,healthy, male and female subjects to evaluate the PK of naloxoneadministered by injection using either the delivery device of presentinvention or a standard syringe was conducted. Thirty (30) healthy adultsubjects completed the study. Subjects were randomized to receive one ofthe following treatments on Day 1 and the alternate treatment on Day 2:

-   -   Treatment A: A single injection of 0.4 mg naloxone HCl for        injection USP administered using a delivery device of the        present invention.    -   Treatment B: A single injection of 0.4 mg naloxone HCl for        injection USP administered using a standard, manually-activated,        syringe.

Randomization was instituted to reduce bias in treatment selection andin evaluation of treatments. The study was conducted in healthy adultmales and females weighing between ≧50 kg and ≦100 kg. The 30 subjectswere randomized to the two treatment sequences, with 15 subjects persequence.

The second dose was administered at least 24 hours after the first doseto permit adequate wash-out between doses. Naloxone is rapidlydistributed in the body and disappears from the serum in the initialdistribution phase over a period of approximately 15 to 20 minutes. Theelimination half-life is estimated to be between 30 and 90 minutes.

The Manual Injection Treatment was naloxone HCl injection USPadministered via standard syringe. The Manual Injection Treatment wasdrawn from International Medicinal Systems (IMS), Limited's 2 mg/2 mLsingle dose disposable LUER-JET naloxone HCl injection USP pre-filledsyringe (National Drug Code number: 0548-1469-00, Abbreviated New DrugApplication #072076). The IMS product is a sterile, non-pyrogenicsolution of naloxone HCl in water for injection. Each mL contains 1.0 mgnaloxone HCl, 8.35 mg/mL sodium chloride to adjust tonicity in water andhydrochloric acid for pH adjustment; pH 3.0-4.5. The IMS product hasbeen approved for IV, IM and SC administration.

The Auto-injection Treatment was naloxone HCl injection USP administeredvia a delivery device of the present invention. This formulation for thenaloxone HCl injection USP utilizes drug substance meeting USP/NationalFormulary and European Pharmacopoeia specifications and the sameexcipients that are approved for the formulation of the ManualInjection. Each mL contains 1.0 mg naloxone HCl, 8.35 mg/mL sodiumchloride to adjust tonicity in water and hydrochloric acid for pHadjustment; pH 3.0-4.5. The parenteral formulation was filled into aType I borosilicate glass cartridge and enclosed with little-to-noheadspace by an elastomeric plunger and elastomeric lined crimp seal(i.e., primary container closure). The materials that made up theprimary container closure for the Auto-Injection Treatment were of thesame general type as those used for the Manual Injection Treatment.

The delivery device and/or drug product had the structure as describedabove for the delivery device 2000 (e.g., the actuation assembly 2500,the medicament container 2200 and the delivery mechanism 2300).Moreover, the gas container included nominally 0.125 grams of Argon at apressure of about 1100 psi (at 70° F.). The dynamic injectionperformance specifications of the drug product for the Auto-InjectionTreatment are shown in Table 2:

TABLE 2 Device Performance Specifications: Test Ave ± SD ActivationForce 7.1 ± 0.5 Volume Dispensed 0.409 ± 0.005 Dispensing Time 0.254 ±0.038 Exposed Needle Length 0.50 ± 0.01

Blood (approximately 7 mL) was collected 5 minutes prior to dosing andat 5, 10, 15, 20, 30, 40 and 50 minutes and 1, 1.25, 1.5, 2, 3, 4 and 6hours post-dose for each dosing period. Blood was processed and plasmaanalyzed by validated methods for concentrations of naloxone and totalnaloxone (naloxone and its major metabolite, naloxone-3-glucuronide).

Pharmacokinetic Plasma Parameters

Pharmacokinetic parameters were calculated by non-compartmental analysismethods from the naloxone plasma concentration-time data using Phoenix®WinNonlin® version 6.2 (Pharsight, St. Louis, Mo., USA) following theseguidelines:

-   -   Actual sampling times relative to dosing were used in the        calculation of all derived PK parameters.    -   There was no imputation of missing data other than the        substitution of concentrations that were BLQ as follows. All        pre-dose BLQ and in the absorption phase prior to the first        quantifiable concentration were substituted by zeros.        Thereafter, BLQ values between quantifiable concentrations were        substituted by ½ of the lower limit of quantification, before        the calculation of the PK variables. The terminal BLQ values        were disregarded.

The below PK parameters were estimated from plasma concentration-actualtime profiles:

-   -   C_(max): Maximum plasma naloxone concentration determined        directly from the plasma concentration-time profile.    -   T_(max): Time of maximum plasma naloxone concentration        determined directly from the plasma concentration-time profile.    -   AUC_(0-t): Area under the plasma concentration-time curve (AUC)        from pre-dose (time 0) to the time of the last quantifiable        concentration (Tlast) calculated using the linear-log        trapezoidal rule.    -   AUC_(0-∞): AUC from pre-dose (time 0) extrapolated to infinite        time (AUC_(0-t)+last observed quantifiable concentration in a        given plasma concentration-time profile [C_(last)]/λ_(z))        calculated using the linear-log trapezoidal rule    -   Lambda z (λ_(z)): Apparent terminal elimination rate constant    -   T_(1/2): Terminal elimination half-life calculated as:        ln(2)/λ_(z)

Analysis of Bioavailability

For each of the naloxone PK parameters C_(max), AUC_(0-t) and AUC_(0-∞),analysis of variance (ANOVA) was applied to thelogarithmically-transformed data and used to test the significance ofthe effects of sequence, period and treatment. In this analysis, subjectnested within sequence was assumed to be a random effect; sequence,period and treatment were modeled as fixed factors. The treatment ratios(Test IMP/Reference IMP) for C_(max), AUC_(0-t) and AUC_(0-∞) werecalculated by taking the anti-logarithm of the difference betweentreatment means.

A 90% CI for the treatment ratio was obtained by taking theanti-logarithm of the 90% CI endpoints for the mean difference.Bioequivalence was suggested when a 90% CI for the ratio of thegeometric least squares (LS) means between treatments was contained inthe equivalence limits (0.8, 1.25) for AUC and Cmax. These equivalencelimits were used as a reference for comparing the bioavailability of thetwo treatments.

All available PK parameter data for AUC and C_(max) was used for theassessment of bioavailability.

Mean plasma plasma concentration-time profiles for naloxone plasmaconcentration data are shown graphically in FIG. 58 (on a linear scale)and FIG. 60 (on a semi-logarithmic scale).

Mean plasma plasma concentration-time profiles for total naloxone plasmaconcentration data (naloxone and its major metabolite,naloxone-3-glucuronide) are presented in FIG. 61 (on linear scales) andFIG. 62 (on semi-logarithmic scales).

Pharmacokinetic parameters are summarized descriptively by treatment inTable 3.

A summary of the statistical analysis of relative bioavailability of thetreatment ratio (Treatment A/Treatment B) of C_(max), AUC_(0-t) andAUC_(0-inf), is presented in Table 4.

TABLE 4 Statistical Analysis of Relative Bioavailability for NaloxonePlasma Pharmacokinetic Parameters 90% CI for Ratio of Within ParameterGeometric Geometric LS Treatment Geometric LS Subject (unit) IMP N LSMeans Means 95% CI Ratio (A/B) Means % CV C_(max) Test 30 1100  (918,1320) 1.15 (0.97, 1.37) 40.9 (pg/mL) Reference 30 957  (797, 1150)AUC_(0-t) Test 30 1780 (1620, 1960) 0.993 (0.94, 1.05) 12.6 (pg · h/mL)Reference 30 1800 (1640, 1970) AUC_(0-inf) Test 30 1880 (1710, 2070)0.983 (0.937, 103)  10.9 (pg · h/mL) Reference 30 1910 (1740, 2110 CI =Confidence interval; % CV = Percentage coefficient of variation; LS:Least squares; N = Number of subjects exposed to treatment; HCl =Hydrochloride; USP = United States Pharmacopeia

What is claimed is:
 1. An apparatus, comprising: a housing; a medicamentcontainer disposed within the housing, the medicament containercontaining a dose of a naloxone composition, the dose having a deliveredvolume of at least 0.34 ml; a needle configured to be placed in fluidcommunication with the medicament container when an end portion of theneedle is extended outside of the housing; and an actuation assemblyincluding an energy storage member and a movable member, the energystorage member configured to produce a force on the movable member todeliver the dose of the naloxone composition from the medicamentcontainer via the needle, the actuation assembly configured to deliverthe dose of the naloxone composition into a body such that release ofthe naloxone composition within the body is bioequivalent to release ofthe naloxone composition resulting from the delivery of a correspondingdose of a corresponding naloxone composition via a manually-actuatedsyringe.
 2. The apparatus of claim 1, wherein the actuation assembly isconfigured to deliver the dose of the naloxone composition into the bodya 90% confidence interval of at least one of a relative mean maximumnaloxone plasma concentration after the dose is delivered into the body(Cmax), a time to reach a maximum naloxone plasma concentration (Tmax),an area under a plasma concentration-time curve from pre-dose (time 0)extrapolated to infinity (AUC0-∞), or an area under the plasmaconcentration-time curve from pre-dose (time 0) to a time of a lastquantifiable concentration (Tlast) (AUC0-t) of the delivered dose to adelivered dose of a corresponding naloxone composition delivered via amanually-actuated syringe is within 80% to 125%.
 3. The apparatus ofclaim 1, wherein the actuation assembly is configured to deliver thedose in less than 0.5 seconds.
 4. The apparatus of claim 1, wherein theactuation assembly is configured such that the force on the movablemember decreases during delivery of the dose from a start force to anend force, the start force being between about between 30 pounds and 38pounds, the end force being between 23 pounds and 31 pounds.
 5. Theapparatus of claim 1, further comprising: a retraction spring configuredto urge the needle towards the first needle position; and a releasemember, the movable member configured to interface with a release memberafter delivery of the dose to release the force from the movable member,the actuation assembly and the release member configured such that atleast 0.34 ml of the naloxone composition is delivered before the needlebegins movement from the second needle position towards the first needleposition.
 6. The apparatus of claim 1, wherein the energy storage memberis any one of a spring, a compressed gas container, or a propellantcontainer.
 7. An apparatus, comprising: a housing; a medicamentcontainer disposed at least partially within the housing, the medicamentcontainer including an elastomeric member disposed therein, themedicament container containing a dose of a naloxone composition, thedose having a delivered volume of at least 0.34 ml; a delivery memberhaving a distal end portion disposed outside of the housing, thedelivery member configured to be placed in fluid communication with themedicament container; and a medicament delivery assembly including amovable member configured to receive an actuation force, the medicamentdelivery assembly including a deformable portion configured to deform inresponse to the force, the movable member configured to move theelastomeric member within the medicament container to deliver thenaloxone composition into a body via the delivery member afterdeformation of the deformable portion, the medicament delivery assemblyconfigured to deliver the dose of the naloxone composition into a bodysuch that a confidence interval of at least one of a maximum naloxoneplasma concentration after the dose is delivered into the body (Cmax), atime to reach the maximum naloxone plasma concentration (Tmax), or anarea under a curve of a naloxone plasma concentration as a function oftime from a first time after the dose is delivered into the body to asecond time after administration (AUC) is between 80 percent and 125percent of a corresponding confidence interval resulting from deliveryof a corresponding dose of a naloxone composition via amanually-actuated syringe, an amount of the corresponding dose beingsubstantially the same as an amount of the dose.
 8. The apparatus ofclaim 7, wherein the delivery member is any one of a needle or a spraynozzle.
 9. The apparatus of claim 7, wherein the delivery member is aneedle, the movable member configured to move the needle from a firstneedle position to a second needle position before the deformation ofthe deformable portion, the distal end portion of the needle disposedoutside of the housing when the needle is in the second needle position.10. The apparatus of claim 7, wherein the medicament delivery assemblyincludes a carrier configured to be coupled to the medicament container,the carrier including the deformable portion.